Novel succinate derivative compounds useful as cysteine protease inhibitors

ABSTRACT

Disclosed are novel succinate derivative compounds of the formula (I)/(Ia):  
                 
 
     wherein R1, R2, R3, R4, R5, R6, R7, X and A are defined herein. The compounds are useful as inhibitors of cysteine proteases. Also disclosed are methods of using and methods of making such compounds.

RELATED APPLICATION DATA

[0001] This application is a divisional of U.S. application Ser. No.09/627,869 filed Jul. 28, 2000.

TECHNICAL FIELD OF THE INVENTION

[0002] This invention relates to peptidyl cysteine protease inhibitors.The compounds are reversible inhibitors of the cysteine proteases S, K,F, L and B and are therefore useful in the treatment of autoimmune andother cathepsin related diseases. The invention also discloses processesfor preparing such compounds and pharmaceutical compositions comprisingthem.

BACKGROUND OF THE INVENTION

[0003] Cathepsin S and cathepsin K are members of the papain family,within the papain superfamily of cysteine proteases. The papain familyis the largest group of cysteine proteases and includes proteases suchas cathepsins B, H, K, L, O and S. (A. J. Barrett et al., 1996,Perspectives in Drug Discovery and Design, 6, 1). The cysteine proteaseshave important roles in human biology and diseases includingatherosclerosis, emphysema, osteoporosis, chronic inflammation andimmune disorders (H. A. Chapman et al., 1997, Ann. Rev. Physiol., 59,63). Cathepsin S plays a key role in regulating antigen presentation andimmunity (H. A. Chapman, 1998, Current Opinion in Immunology, 10, 93; R.J. Riese et al., 1998, J. Clin. Invest., 101, 2351; R. J. Riese et al.,1996, Immunity, 4, 357). Cathepsin S deficient mice have impairedinvariant chain degradation resulting in decreased antigen presentationand germinal center formation, and diminished susceptibility tocollagen-induced arthritis indicating the therapeutic potential for acathepsin S inhibitor (G. Shi et al., 1999, Immunity, 10, 197; T. Y.Nakagawa et al, 1999, Immunity, 10, 207)

[0004] The specificity of the immune response relies on processing offoreign protein and presentation of antigenic peptide at the cellsurface. Antigenic peptide is presented bound to MHC Class II, aheterodimeric glycoprotein expressed in certain antigen presenting cellsof hematopoietic lineage, such as B cells, macrophages and dendriticcells. Presentation of antigen to effector cells, such as T-cells, is afundamental step in recognition of non-self and thus initiation of theimmune response.

[0005] Recently MHC Class II heterodimers were shown to associateintracellularly with a third molecule designated invariant chain.Invariant chain facilitates Class II transport to the endosomalcompartment and stabilizes the Class II protein prior to loading withantigen. Invariant chain interacts directly with Class II dimers in theantigen-binding groove and therefore must be proteolyzed and removed orantigen cannot be loaded or presented. Current research suggests thatinvariant chain is selectively proteolyzed by cathepsin S, which iscompartmentalized with MHC Class II complexes within the cell. CathepsinS degrades invariant chain to a small peptide, termed CLIP, whichoccupies the antigen—binding groove. CLIP is released from MHC Class IIby the interaction of MHC Class II with HLA-DM, a MHC-like molecule thusfreeing MHC Class II to associate with antigenic peptides. MHC ClassII-antigen complexes are then transported to the cell surface forpresentation to T-cells, and initiation of the immune response.

[0006] Cathepsin S, through proteolytic degradation of invariant chainto CLIP, provides a fundamental step in generation of an immuneresponse. It follows that inhibition of antigen presentation viaprevention of invariant chain degradation by cathepsin S could provide amechanism for immuno-regulation. Control of antigen-specific immuneresponses has long been desirable as a useful and safe therapy forautoimmune diseases. Such diseases include Crohn's disease andarthritis, as well as other T-cell-mediated immune responses (C. Janewayand P. Travers, 1996, Imunobiology, The Immune System in Health andDisease, Chapter 12). Furthermore, cathepsin S, which has broad pHspecificity, has been implicated in a variety of other diseasesinvolving extracellular proteolysis, such as Alzheimer's disease (U.Muller-Ladner et al., 1996, Perspectives in Drug Discovery and Design,6, 87) and atherosclerosis (G. K. Sukhova et al., 1998, J. Clin.Invest., 102, 576).

[0007] A cathepsin S inhibitor has been found to block the rise in IgEtiters and eosinophil infiltration in the lung in a mouse model ofpulmonary hypersensitivity, suggesting that cathepsin S may be involvedin asthma (R. J. Riese et al., J. Clin. Investigation,1998, 101, 2351).

[0008] Another cysteine protease, cathepsin F has been found inmacrophages and is also involved in antigen processing. It has beenpostulated that cathepsin F in stimulated lung macrophages and possiblyother antigen presenting cells could play a role in airway inflammation(G. -P. Shi et al., J. Exp. Med., 2000, 191, 1177).

[0009] Cathepsin K, another cysteine protease has been found to behighly expressed in osteoclasts and to degrade bone collagen and otherbone matrix proteins. Inhibitors of cathepsin K have been shown toinhibit bone resorption in mice. Therefore, cathepsin K may play a rolein osteoclastic bone resorption and cathepsin K inhibitors may be usefulin the treatment of diseases involving bone resorption such asosteoporosis (F. Lazner et al., Human Molecular Genetics, 1999, 8,1839).

[0010] Cysteine proteases are characterized by having a cysteine residueat the active site which serves as a nucleophile. The active site alsocontains a histidine residue. The imidazole ring on the histidine servesas a base to generate a thiolate anion on the active site cysteine,increasing its nucleophilicity. When a substrate is recognized by theprotease, the amide bond to be cleaved is directed to the active site,where the thiolate attacks the carbonyl carbon forming an acyl-enzymeintermediate and cleaving the amide bond, liberating an amine.Subsequently, water cleaves the acyl-enzyme species regenerating theenzyme and liberating the other cleavage product of the substrate, acarboxylic acid.

[0011] Inhibitors of cysteine proteases contain a functionality that canreact reversibly or irreversibly with the active site cysteine. Examplesof reactive functionalities that have been described (D. Rasnick, 1996,Perspectives in Drug Discovery and Design, 6, 47) on cysteine proteaseinhibitors include peptidyl diazomethanes, epoxides, monofluoroalkanesand acyloxymethanes, which irreversibly alkylate the cysteine thiol.Other irreversible inhibitors include Michael acceptors such as peptidylvinyl esters and other carboxylic acid derivatives (S. Liu et al., J.Med Chem., 1992, 35, 1067) and vinyl sulfones (J. T. Palmer et al.,1995, J. Med Chem., 38, 3193).

[0012] Reactive functionalities that form reversible complexes with theactive site cysteine include peptidyl aldehydes (R. P. Hanzlik et al.,1991, Biochim. Biophys. Acta., 1073, 33), which are non-selective,inhibiting both cysteine and serine proteases as well as othernucleophiles. Peptidyl nitriles (R. P. Hanzlik et al., 1990, Biochim.Biophys. Acta., 1035, 62) are less reactive than aldehydes and thereforemore selective for the more nucleophilic cysteine proteases. Variousreactive ketones have also been reported to be reversible inhibitors ofcysteine proteases (D. Rasnick, 1996, ibid). In addition to reactingwith the nucleophilic cysteine of the active site, reactive ketones mayreact with water, forming a hemiketal which may act as a transitionstate inhibitor.

[0013] Examples of cathepsin S inhibitors have been reported. J. L.Klaus et al. (WO 9640737) described reversible inhibitors of cysteineproteases including cathepsin S, containing an ethylene diamine. In U.S.Pat. No. 5,776,718 to Palmer et al. there is disclosed in it's broadestgeneric aspect a protease inhibitor comprising a targeting group linkedthrough a two carbon atom chain to an electron withdrawing group (EWG).The compounds of the present application are structurally distinct andthus excluded from the U.S. Pat. No. 5,776,718 patent with particularembodiments possessing unexpectedly greater activity than the closestcompounds of the prior art. Other examples of cathepsin S inhibitorshave been reported by E. T. Altmann et al, (WO 9924460, 1999) whichdescribes dipeptide nitriles asserted to have activity as inhibitors ofCathepsins B, K, L and S. The WO publication does not disclose anycompounds possessing a succinate structure.

[0014] Additional peptidyl nitriles have been reported as proteaseinhibitors. For example, both nitriles and ketoheterocycles aredescribed by B. A. Rowe et al. (U.S. Pat. No. 5,714,471) as proteaseinhibitors useful in the treatment of neurodegenerative diseases.Peptidyl nitriles are reported by B. Malcolm et al. (WO 9222570) asinhibitors of picomavirus protease. B. J. Gour-Salin (Can. J. Chem.,1991, 69, 1288) and T. C. Liang (Arch. Biochim. Biophys., 1987, 252,626) described peptidyl nitrites as inhibitors of papain

[0015] A reversible inhibitor presents a more attractive therapy thanirreversible inhibitors. Even compounds with high specificity for aparticular protease can bind non-target enzymes. An irreversiblecompound could therefore permanently inactivate a non-target enzyme,increasing the likelihood of toxicity. Furthermore, any toxic effectsresulting from inactivation of the target enzyme would be mitigated byreversible inhibitors, and could be easily remedied by modified or lowerdosing. Finally, covalent modification of an enzyme by an irreversibleinhibitor could potentially generate an antibody response by acting as ahapten.

[0016] In light of the above, there is a clear need for compounds whichreversibly and selectively inhibit cysteine proteases such as cathepsinS, K, F, L and cathepsin B for indications in which these proteasesexacerbate disease.

SUMMARY OF THE INVENTION

[0017] It is therefore an object of this invention to provide novelcompounds according to the formulas (I) and (Ia) as described hereinwhich reversibly inhibit the cysteine proteases cathepsin S , K, F, Land cathepsin B. It is a further object of the invention to providemethods for treating diseases and pathological conditions exacerbated bythese cysteine proteases such as, but not limited, to rheumatoidarthritis, asthma and osteoporosis. It is yet a further object of theinvention to provide novel processes for preparation of theabove-mentioned novel compounds.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The novel compounds of the invention are derivatives ofsuccinamide and are therefore less peptidic in nature than many of theprotease inhibitors described in the prior art. These compounds, then,may exhibit certain advantages over known peptidic like compounds. Theseadvantages may include, for example, increased bioavailability,increased stability, increased half-life and decreased clearance rates.

[0019] A proposed mechanism of action of the cysteine proteaseinhibitors of this invention is that the inhibitors contain afunctionality that can react (reversibly or irreversibly) with theactive site cysteine. The reactive functionality is attached to apeptide or peptide mimic that can be recognized and accommodated by theregion of the protease surrounding the active site. The nature of boththe reactive functionality and the remaining portion of the inhibitordetermine the degree of selectivity and potency toward a particularprotease.

[0020] Given the similarity of the active sites in cysteine proteases,it may be anticipated that a given class of inhibitors might haveactivity against more that one cysteine protease. It may also beexpected that due to structural differences between individual cysteineproteases, different compounds of the invention may have differentinhibitory potencies against different cysteine proteases. Thus some ofthe compounds of the invention may also be expected to be most effectivein treating diseases mediated by cysteine proteases that they inhibitmost potently. The activity of particular compounds disclosed hereinagainst cysteine proteases cathepsin S, K, F, L and cathepsin B may bedetermined by the screens described in the section entitled “Assessmentof Biological Properties.”

[0021] Accordingly, in the first generic aspect of the invention, thereis provided compounds of formula (I):

[0022] wherein:

[0023] A is —C(O)— or —CH(OR8)—;

[0024] R1 is alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or aminowherein R1 is optionally substituted by one or more R_(a);

[0025] R_(a) is selected from the group consisting of alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkanoyl, aroyl,alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byalkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino,alkylthio arylthio, ureido wherein either nitrogen atom may beindependently substituted by alkyl, aryl, heterocyclyl or heteroaryl,alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy,arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl, heterocyclylor heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino; R_(a) may be further optionally substituted by one or moreR_(b);

[0026] R_(b) is selected from the group consisting of alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy,alkanoyl, aroyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;

[0027] R2 is hydrogen, ORi or lower alkyl;

[0028] R3 is hydrogen or lower alkyl;

[0029] R4 is hydrogen or lower alkyl;

[0030] R5 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl, wherein R5 is optionally substituted by one or more R_(c);

[0031] R_(c) is selected from the group consisting of alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy,alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by alkyl, aryl, heterocyclyl or heteroaryl,alkanoylamino, aroylamino, alkylthio, arylthio, ureido wherein eithernitrogen atom may be independently substituted by alkyl, aryl,heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino,alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino,arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino whereinthe nitrogen atom may be independently mono or di-substituted by alkyl,aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino, R_(c) may be further optionallysubstituted by one or more R_(d);

[0032] R_(d) is selected from the group consisting of alkyl, cycloalkyl,aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;

[0033] R6 is hydrogen or lower alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S;

[0034] R7 is hydrogen, alkyl said alkyl being optionally interrupted by1 to two heteroatoms selected from the group consisting of N, O and S,cycloalkyl, aryl, heterocyclyl, aryl, heteroaryl or cyano, wherein R7 isoptionally substituted by one or more R_(e);

[0035] R_(e) is selected from the group consisting of alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkanoyl,aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy,heteroarylalkoxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by alkyl, aryl, heterocyclyl orheteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl,alkylthio, arylthio, arylalkylthio, ureido wherein either nitrogen atommay be independently substituted by alkyl, aryl, heterocyclyl orheteroaryl, alkoxycarbonylamino, aryloxycarbonylamino,alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino,arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino whereinthe nitrogen atom may be independently mono or di-substituted by alkyl,aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino, R_(e) may be further optionallysubstituted by one or more R_(f);

[0036] R_(f) is selected from the group consisting of alkyl, cycloalkyl,aryl optionally substituted by one or more groups selected from halogen,methyl or methoxy, heterocyclyl, heteroaryl, alkoxy, aryloxy,arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by alkyl, aryl, heterocyclyl or heteroaryl,alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by alkyl, aryl, heterocyclyl or heteroaryl,alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy,arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl, heterocyclylor heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino;

[0037] or R6 and R7 together with the carbon they are attached form a 4to 7 membered carbocyclic or heterocyclic ring, the carbocyclic orheterocyclic ring being optionally substituted with one or more R_(g);

[0038] R_(g) is selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, imidazolyl and pyridinyl, C1-5 alkanoyl, aroyl, C1-5alkoxycarbonyl, aryloxycarbonyl, carbamoyl wherein the nitrogen atom maybe independantly mono or disubstituted by C1-5 alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl and piperazinyl or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl,pyridinyl, benzimidazolyl and quinolinyl, C1-5 alkanoylamino,aroylamino, C1-5 alkylthio, arylthio, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or disubstituted byalkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl, or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino, R_(g) may be further optionallysubstituted by one or more R_(h);

[0039] R_(h) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, aryl optionally substituted by one or more groups selectedfrom halogen, lower alkyl or lower alkoxy, heterocyclyl selected fromthe group consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl,heteroaryl selected from the group consisting of furanyl, thienylpyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl andquinoxalinyl, C1-5 alkoxy, aryloxy, amino wherein the nitrogen atom maybe independently mono or di-substituted by alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl andmorpholinyl, or heteroaryl selected from the group consisting offuranyl, thienyl, pyrrolyl and pyridinyl, halogen, hydroxy, oxo,carboxy, cyano, nitro, amidino and guanidino;

[0040] R8 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl oraryl-alkyl;

[0041] Ri is hydrogen or lower alkyl;

[0042] X is O or S and

[0043] pharmaceutically acceptable salts, esters or tautomers thereof.

[0044] Preferred are compounds of the formula (I)

[0045] wherein:

[0046] A is as defined above;

[0047] R1 is C1-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selectedfrom the group consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl,heteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl and amino wherein R1 is optionallysubstituted by one or more R_(a);

[0048] R_(a) is selected from the group consisting of C1-8 alkyl, C3-7cycloalkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl, heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, C1-8alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-8 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino,aroylamino, C1-8 alkylthio, arylthio, ureido wherein either nitrogenatom may be independently substituted by alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyland phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino,alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino,arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino whereinthe nitrogen atom may be independently mono or di-substituted by alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo,carboxy, cyano, nitro, amidino and guanidino; R_(a) may be furtheroptionally substituted by one or more R_(b);

[0049] R_(b) is selected from the group consisting of C1-8 alkyl, C3-6cycloalkyl, aryl, C1-8 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy,cyano, nitro, amidino and guanidino;

[0050] R2 is hydrogen, ORi or C1-5 alkyl;

[0051] R3 is hydrogen or C1-5 alkyl;

[0052] R4 is hydrogen or C1-5 alkyl;

[0053] R5 is hydrogen, C1-8 alkyl, C3-7 cycloalkyl or aryl wherein R5 isoptionally substituted by one or more R_(c);

[0054] R_(c) is selected from the group consisting of C1-8 alkyl, C3-7cycloalkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl; heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy,alkanoyl, aroyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy,aroyloxy, carbamoyl wherein the nitrogen atom may be independently monoor di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,C1-8 alkanoylamino, aroylamino, C1-8 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by alkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, alkoxycarbonylamino,aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy,alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino,R_(c) may be further optionally substituted by one or more R_(d);

[0055] R_(d) is selected from the group consisting of C1-8 alkyl, C3-6cycloalkyl, aryl, arylalkyl, C1-8 alkoxy, aryloxy, arylalkoxy, aroyl,amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino;

[0056] R7 is hydrogen, C1-8 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S, C3-7 cycloalkyl, aryl or cyano, wherein R7 is optionallysubstituted by one or more R_(e);

[0057] R_(e) is selected from the group consisting of C1-8 alkyl, C3-7cycloalkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl, heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy,arylC1-8alkoxy, heteroarylC1-8alkoxy, C1-8 alkoxycarbonyl,aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-8 alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8alkylthio, arylthio, arylC1-8 alkylthio, ureido wherein either nitrogenatom may be independently substituted by alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyland phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino,alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino,arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino whereinthe nitrogen atom may be independently mono or di-substituted by alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino, R_(e) may be further optionallysubstituted by one or more R_(f);

[0058] R_(f) is selected from the group consisting of C1-8 alkyl, C3-7cycloalkyl, aryl optionally substituted by one or more groups selectedfrom halogen, methyl or methoxy, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl, heteroaryl selected from the group consistingof furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy,arylC1-8alkoxy, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy,aroyloxy, carbamoyl wherein the nitrogen atom may be independently monoor di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,C1-8 alkanoylamino, aroylamino, C1-8 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by alkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, alkoxycarbonylamino,aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy,alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;

[0059] or R6 and R7 together with the carbon they are attached form a 4to 7 membered carbocyclic or heterocyclic ring, the carbocyclic orheterocyclic ring being optionally substituted with one or more R_(g);

[0060] R_(g) is selected from the group consisting of alkyl, cycloalkyl,phenyl, heteroaryl selected from the group consisting of furanyl,thienyl and pyridinyl, C1-5alkanoyl, aroyl, C1-5alkoxycarbonyl,aryloxycarbonyl, carbamoyl wherein the nitrogen atom may beindependantly mono or disubstituted by C1-5 alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl and piperazinyl or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl,pyridinyl, benzimidazolyl and quinolinyl, C1-5 alkylthio wherein thesulfur atom may be oxidised to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidised to a sulfoxide or sulfone, C1-5alkylaminosulfonyl, arylaminosulfonyl, halogen, hydroxy, oxo, carboxyand cyano, R_(g) may be further optionally substituted by one or moreR_(h);

[0061] R_(h) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, aryl optionally substituted by one or more groups selectedfrom halogen, C1-5 alkyl or C1-5 alkoxy, heterocyclyl selected from thegroup consisting of piperidinyl, morpholinyl and piperazinyl, heteroarylselected from the group consisting of furanyl, thienyl pyrrolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl,quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl and quinoxalinyl,C1-5 alkoxy, aryloxy, amino wherein the nitrogen atom may beindependently mono or di-substituted by alkyl, aryl, heterocyclylselected from the group consisting of piperidinyl and morpholinyl orheteroaryl selected from the group consisting of furanyl, thienyl andpyridinyl, halogen, hydroxy, oxo, carboxy and cyano;

[0062] R8 is hydrogen, alkyl, cycloalkyl-alkyl or arylalkyl;

[0063] Ri is hydrogen or C1-8 alkyl and

[0064] X is O or S.

[0065] More preferred are compounds of the formula (I) as describedimmediately above and wherein:

[0066] A is as defined above;

[0067] R1 is C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl andthiopyranyl, heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl or amino; wherein R1 is optionallysubstituted by one or more R_(a);

[0068] R_(a) is selected from the group consisting of C1-5 alkyl, C3-7cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl;, heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy,aryloxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy,aroyloxy, carbamoyl wherein the nitrogen atom may be independently monoor di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido whereineither nitrogen a tom may b e independently substituted by alkyl, aryl,heterocycly selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byalkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino, R_(a) may be further optionallysubstituted by one or more R_(b);

[0069] R_(b) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, aryl, C1-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy,cyano, nitro, amidino and guanidino;

[0070] R2 is hydrogen, ORi or C1-3 alkyl;

[0071] R3 is hydrogen or C1-3 alkyl;

[0072] R4 is hydrogen or C1-3 alkyl;

[0073] R5 is hydrogen, C1-5 alkyl, C3-7 cycloalkyl or aryl wherein R5 isoptionally substituted by one or more R_(c);

[0074] R_(c) is selected from the group consisting of C1-5 alkyl, C3-7cycloalyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl, heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy, C1-5 alkanoyl,aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl, or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by C1-5 alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano,amidino and guanidino, R_(c) may be further optionally substituted byone or more R_(d);

[0075] R_(d) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, aryl, arylalkyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy,aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino;

[0076] R6 is hydrogen or C1-8 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S;

[0077] R7 is hydrogen, C1-5 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S, C3-7 cycloalkyl, aryl or cyano, wherein R7 is optionallysubstituted by one or more R_(e);

[0078] R_(e) is selected from the group consisting of C1-5 alkyl, C3-7cycloalkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl; heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy,heteroarylC1-5alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkanoylamino, aroylamino, C1-5alkylthioarylthioarylC1-5 alkylthio, ureido wherein either nitrogen atommay be independently substituted by C1-5 alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino, R_(e) may be further optionallysubstituted by one or more R_(f);

[0079] R_(f) is selected from the group consisting of C1-5 alkyl, C3-7cycloalkyl, aryl optionally substituted by one or more groups selectedfrom halogen, methyl or methoxy, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl, heteroaryl selected from the group consistingof furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy,arylC1-5alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy,aroyloxy, carbamoyl wherein the nitrogen atom may be independently monoor di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by C1-5 alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino;

[0080] or R6 and R7 together with the carbon they are attached form acarbocyclic ring selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl or a heterocyclic ring selectedfrom the group consisting of pyrrolidinyl, piperidinyl,hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, pyranyl,thiopyranyl, 1,2-thiazinanyl-1,1-dioxide,1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide andimidazolidinyl-2,4-dione, the carbocyclic or heterocyclic ring beingoptionally substituted with one or more R_(g);

[0081] R_(g) is selected from the group consisting of alkyl, cycloalkyl,phenyl, heteroaryl selected from the group consisting of furanyl andthienyl, C1-3 alkanoyl, benzoyl, C1-3 alkoxycarbonyl, carbamoyl whereinthe nitrogen atom may be independantly mono or disubstituted by C1-5alkyl, phenyl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl and pyridinyl, C1-3 alkylthiowherein the sulfur atom may be oxidised to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidised to a sulfoxide orsulfone, C1-5 alkylaminosulfonyl, phenylaminosulfonyl, halogen, hydroxy,carboxy and cyano, R_(g) may be further optionally substituted by one ormore R_(h);

[0082] R_(h) is selected from the group consisting of C1-3 alkyl, C5-6cycloalkyl, phenyl optionally substituted by one or more groups selectedfrom halogen, C1-3 alkyl and C1-3 alkoxy, piperidinyl, morpholinyl,piperazinyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,benzimidazolyl, quinolinyl, isoquinolinyl, C1-3 alkoxy, amino whereinthe nitrogen atom may be independently mono or di-substituted by C1-5alkyl, phenyl, heterocyclyl selected from the group consisting ofpiperidinyl and morpholinyl or heteroaryl selected from the groupconsisting of furanyl, thienyl and pyridinyl, halogen, hydroxy, oxo andcyano.

[0083] R8 is hydrogen, C1-8 alkyl, C3-6 cycloalkyl-alkyl or aryl C1-3alkyl; and

[0084] Ri is hydrogen or C1-5 alkyl.

[0085] Even more preferred are compounds of the formula (I) as describedimmediately above and wherein:

[0086] A is as defined above;

[0087] R1 is C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl or amino wherein R1 is optionally substituted by one ormore R_(a);

[0088] R_(a) is selected from the group consisting of C1-5 alkyl, C3-7cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl, heteroaryl selected from the group consistingof furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkoxy, aryloxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy,aroyloxy, carbamoyl wherein the nitrogen atom may be independently monoor di-substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclyl selectedfrom the group consisting of pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl and indolinyl or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by alkyl or aryl,C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy,arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, R_(a)may be further optionally substituted by one or more R_(b);

[0089] R_(b) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, aryl, C1-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxyand cyano;

[0090] R2 is hydrogen, ORi or methyl;

[0091] R3 is hydrogen or methyl;

[0092] R4 is hydrogen or methyl;

[0093] R5 is C1-5 alkyl, C3-7 cycloalkyl or phenyl wherein R5 isoptionally substituted by one or more R_(c);

[0094] R_(c) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of piperidinyl, morpholinyl and piperazinyl; heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl, C1-5 alkoxy, aryloxy, aroyl, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by C1-5 alkyl,phenyl, naphthyl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl or heteroaryl selected thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy,arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-5 alkyl, phenyl,naphthyl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen,hydroxy, oxo, carboxy and cyano, R_(c) may be further optionallysubstituted by one or more R_(d);

[0095] R_(d) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, aryl, arylC1-5alkyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy,aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano;

[0096] R6 is hydrogen or C1-5 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S;

[0097] R7 is hydrogen, C1-5 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S, C3-7 cycloalkyl, phenyl, naphthyl or cyano, wherein R7 isoptionally substituted by one or more R_(e);

[0098] R_(e) is selected from the group consisting of C1-5 alkyl, C3-7cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl, heteroaryl selected from the group consistingof furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy,arylC1-5alkoxy, heteroarylC1-5alkoxy, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,aryl, heterocyclyl selected from the group consisting of piperidinyl,morpholinyl and piperazinyl or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, arylC1-5 alkylthio,ureido wherein either nitrogen atom may be independently substituted byC1-5 alkyl, aryl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy,arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-5 alkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen,hydroxy, oxo, carboxy and cyano, R_(e) may be her optionally substitutedby one or more R_(f);

[0099] R_(f) is selected from the group consisting of C1-5 alkyl, C3-7cycloalkyl, phenyl optionally substituted by one or more groups selectedfrom halogen, methyl and methoxy, naphthyl optionally substituted by oneor more groups selected from halogen, methyl and methoxy, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy, C1-5alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by C1-5 alkyl,aryl, heterocyclyl selected from the group consisting of piperidinyl,morpholinyl and piperazinyl or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy,arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-5 alkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen,hydroxy, oxo, carboxy and cyano;

[0100] or R6 and R7 together with the carbon they are attached form acarbocyclic ring selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl or a heterocyclic ring selectedfrom the group consisting of piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, piperazinyl, pyranyl and thiopyranyl, thecarbocyclic or heterocyclic ring being optionally substituted with oneor more R_(g);

[0101] R_(g) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, C1-3 alkanoyl, benzoyl, C1-3 alkoxycarbonyl, carbamoylwherein the nitrogen atom may be independantly mono or disubstituted byC1-5 alkyl, phenyl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl and pyridinyl, halogen, hydroxy,carboxy and cyano, R_(g) may be further optionally substituted by one ormore R_(h);

[0102] R_(h) is selected from the group consisting of methyl, phenyloptionally substituted by one or more groups selected from halogen,methyl and methoxy, piperidinyl, morpholinyl, piperazinyl, pyridinyl,amino wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl, phenyl, heterocyclyl selected from thegroup consisting of piperidinyl and morpholinyl or heteroaryl selectedfrom the group consisting of furanyl, thienyl and pyridinyl, halogen,hydroxy, oxo and cyano;

[0103] R8 is hydrogen, C1-5 alkyl, C5-6 cycloalkyl-C1-3-alkyl or benzyl;

[0104] Ri is hydrogen or methyl; and

[0105] X is O.

[0106] Yet even more preferred are compounds of the formula (I) asdescribed immediately above and wherein:

[0107] A is as defined above;

[0108] R1 is C1-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl,piperazinyl, pyranyl and thiopyranyl, heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl or amino,wherein R1 is optionally substituted by one or more R_(a);

[0109] R_(a) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl,heteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl and isoquinolinyl, C1-3 alkoxy, phenoxy, C1-3 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,phenyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyland isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio,arylthio, ureido wherein either nitrogen atom may be independentlysubstituted by C1-5alkyl, phenyl or naphthyl, C1-5 alkoxycarbonylamino,C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5alkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of piperidinyl, morpholinyl and piperazinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, R_(a) may befurther optionally substituted by one or more R_(b);

[0110] R_(b) is selected from the group consisting of C1-3 alkyl, C5-6cycloalkyl, aryl, C1-3 alkoxy, phenoxy, halogen, hydroxy, oxo, carboxyand cyano;

[0111] R2 is hydrogen or ORi;

[0112] R3 is hydrogen;

[0113] R4 is hydrogen;

[0114] R5 is C1-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R5 isoptionally substituted by one or more R_(c);

[0115] R_(c) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of piperidinyl, morpholinyl and piperazinyl, heteroarylselected from the group consisting of furanyl, thienyl, thiazolyl,imidazolyl, pyridinyl, indolyl, quinolinyl and isoquinolinyl, C1-5alkoxy, phenoxy, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, phenyl, naphthyl,heterocyclyl selected from the group consisting of piperidinyl,morpholinyl and piperazinyl or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl and indolyl, C1-5 alkanoylamino, aroylamino, C1-3alkylthio, phenylthio, ureido wherein either nitrogen atom may beindependently substituted by C1-3 alkyl, phenyl or heteroaryl selectedthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl and indolyl, C1-5 alkoxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-3 alkyl, phenyl, heterocyclyl selected fromthe group consisting of piperidinyl, morpholinyl and piperazinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl,halogen, hydroxy, oxo, carboxy and cyano, R_(c) may be furtheroptionally substituted by one or more R_(d);

[0116] R_(d) is selected from the group consisting of C1-5 alkyl, C5-6cycloalkyl, phenyl, naphthyl, arylC1-3alkyl, C1-5 alkoxy, phenoxy,arylC1-3alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano;

[0117] R6 is hydrogen or C1-3alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S;

[0118] R7 is hydrogen, C1-5 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S, C3-6 cycloalkyl, phenyl or cyano, wherein R7 isoptionally substituted by one or more R_(e);

[0119] R_(e) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl,heteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyland isoquinolinyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy,heteroarylC1-3alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, phenyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5alkanoylamino, aroylamino, C1-3 alkylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, arylthio, arylC1-3alkylthio, ureidowherein either nitrogen atom may be independently substituted by C1-5alkyl or phenyl, C1-5 alkoxycarbonylamino, C1-5 alkylsulfonylamino,arylsulfonylamino, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl andpiperazinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, andindolyl, halogen, hydroxy, oxo, carboxy and cyano, R_(e) may be furtheroptionally substituted by one or more R_(f);

[0120] R_(f) is selected from the group consisting of C1-3 alkyl, C5-6cycloalkyl, phenyl optionally substituted by one or more groups selectedfrom halogen and methyl, heterocyclyl selected from the group consistingof pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl andindolyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkylor aryl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio,ureido wherein either nitrogen atom may be independently substituted byC1-5 alkyl or aryl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl or aryl, halogen, hydroxy, oxo, carboxy and cyano; or

[0121] R6 and R7 together with the carbon they are attached form acarbocyclic ring selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl or heterocyclic ring selectedfrom the group consisting of piperidinyl, morpholinyl andthiomorpholinyl, the carbocyclic or heterocyclic ring being optionallysubstituted with one or more R_(g);

[0122] R_(g) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, C1-3 alkanoyl, C1-3 alkoxycarbonyl and carbamoyl wherein thenitrogen atom may be independantly mono or disubstituted by C1-5 alkyl;R_(g) may be further optionally substituted by one or more R_(h);

[0123] R_(h) is phenyl or amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl;

[0124] R8 is hydrogen or methyl;

[0125] Ri is hydrogen or methyl and

[0126] and X is O.

[0127] Still yet even more preferred are compounds of the formula (I) asdescribed immediately above and wherein:

[0128] A is as defined above;

[0129] R1 is C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl,piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl and indolyl or amino, wherein R1 is optionallysubstituted by one or more R_(a);

[0130] R_(a) is selected from the group consisting of C1-3 alkyl, C5-6cycloalkyl, phenyl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl, heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrazolyl,pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl and isoquinolinyl, C1-3 alkoxy, C1-3alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl or heteroaryl selected from the group consisting ofpyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl and benzthiazolyl, C1-5 alkanoylamino, aroylamino, C1-3alkylthio, arylthio, ureido wherein either nitrogen atom may beindependently substituted by C1-3alkyl or phenyl, C1-5alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3alkyl, phenyl,heterocyclyl selected from the group consisting of piperidinyl,morpholinyl and piperazinyl or heteroaryl selected from the groupconsisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, R_(a) may befurther optionally substituted by one or more R_(b);

[0131] R_(b) is selected from the group consisting of C1-3 alkyl, C5-6cycloalkyl, C1-3 alkoxy, halogen and hydroxy;

[0132] R2 is hydrogen;

[0133] R3 and R4 are as defined immediately above;

[0134] R5 is C1-5 alkyl, C5-6 cycloalkyl or phenyl wherein R5 isoptionally substituted by one or more R_(c);

[0135] R_(c) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, phenyl, naphthyl, 4-piperidinyl, 4-morpholinyl, piperazinyl,furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, C1-5alkoxy, phenoxy, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl or phenyl, C1-5alkanoylamino, C1-3 alkylthio, ureido wherein either nitrogen atom maybe independently substituted by C1-3 alkyl or phenyl, C1-5alkoxycarbonylamino, C1-5 alkylsulfonylamino, arylsulfonylamino, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, R_(c)may be further optionally substituted by one or more R_(d);

[0136] R_(d) is selected from the group consisting of C1-5 alkyl, C5-6cycloalkyl, phenyl, benzyl, C1-5 alkoxy, phenoxy, benzyloxy, aroyl,halogen, hydroxy, oxo, carboxy and cyano;

[0137] R6 is hydrogen or C1-3alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S;

[0138] R7 is hydrogen, C1-5 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S, phenyl or cyano, wherein R7 is optionally substituted byone or more R_(e);

[0139] R_(e) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl,pyridinyl, indolyl, C1-3 alkoxy, benzyloxy, pyridylC1-3alkoxy,thienylC1-3alkoxy, furanylC1-3alkoxy, C1-3 alkoxycarbonyl,phenoxyoxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkylor phenyl, C1-5 alkanoylamino, aroylamino, methylthio, benzylthio,ureido wherein either nitrogen atom may be independently substituted byC1-5 alkyl or phenyl, C1-3 alkoxycarbonylamino, amino wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkylor phenyl, halogen, hydroxy, oxo, carboxy and cyano, R_(e) may befurther optionally substituted by one or more R_(f);

[0140] R_(f) is selected from the group consisting of C1-3 alkyl, phenyloptionally substituted by one or more groups selected from the groupconsisting of halogen and methyl, heterocyclyl selected from the groupconsisting of piperidinyl, morpholinyl and piperazinyl, heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl andpyridinyl, C1-3 alkoxy, aryloxy, benzyloxy, C1-5 alkoxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl or phenyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, ureido wherein eithernitrogen atom may be independently substituted by C1-5 alkyl or phenyl,C1-5 alkoxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-3alkylsulfonylamino, arylsulfonylamino, C1-3 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy, oxo,carboxy and cyano;

[0141] or R6 and R7 together with the carbon they are attached formcyclopropyl or a heterocyclic ring selected from the group consisting ofpiperidinyl, pyranyl and thiopyranyl, the cyclopropyl or heterocyclicring being optionally substituted with one or more R_(g);

[0142] R_(g) is selected from the group consisting of methyl, benzyl,acetyl, benzoyl, benzyloxycarbonyl and ethoxycarbonyl;

[0143] R8 is hydrogen and

[0144] X is O.

[0145] Even much more preferred are compounds of the formula (I) asdescribed immediately above and wherein:

[0146] A is as described above;

[0147] R1 is C3-6 cycloalkyl, phenyl, naphthyl, piperidinyl,morpholinyl, piperazinyl, pyranyl, thiopyranyl, furanyl, thienyl,pyrrolyl or amino, wherein R1 is optionally substituted by one or moreR_(a);

[0148] R_(a) is selected from the group consisting of C1-3 alkyl, C5-6cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, C1-3 alkoxy,C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or phenyl, C1-5alkanoylamino, aroylamino, ureido wherein either nitrogen atom may beindependently substituted by C1-3alkyl or phenyl, C1-5alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3alkyl or phenyl,halogen, hydroxy, oxo, carboxy and cyano, R_(a) may be furtheroptionally substituted by one or more R_(b);

[0149] R_(b) is selected from the group consisting of C1-3alkyl,C1-3alkoxy, halogen and hydroxy;

[0150] R2, R3 and R4 are as defined immediately above;

[0151] R5 is C1-5 alkyl, C5-6 cycloalkyl or phenyl, wherein R5 isoptionally substituted by one or more groups of the formula R_(c);

[0152] R_(c) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, phenyl, naphthyl, 4-piperidinyl, furanyl, thienyl,thiazolyl, imidazolyl, pyridinyl, indolyl, C1-3 alkoxy, C1-5alkoxycarbonyl, C1-5 alkanoyloxy, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkylor phenyl, C1-5 alkanoylamino, C1-3 alkylthio, C1-3 alkoxycarbonylamino,C1-3 alkylsulfonylamino, amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or phenyl, halogen,hydroxy, oxo, carboxy and cyano, R_(c) may be further optionallysubstituted by one or more R_(d);

[0153] R_(d) is selected from the group consisting of C1-3 alkyl,phenyl, benzyl, C1-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen,hydroxy, oxo, carboxy and cyano;

[0154] wherein the configuration at the stereocenter defined by R4 andR5 and the carbon they are attached to is defined as L;

[0155] R6 is hydrogen or C1-2 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S;

[0156] R7 is C1-5 alkyl said alkyl being optionally interrupted by 1 totwo heteroatoms selected from the group consisting of N, O and S; phenylor cyano wherein R7 is optionally substituted by one or more groups ofthe formula R_(e);

[0157] R_(e) is selected from the group consisting of methyl, C3-6cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl,pyridinyl, indolyl, C1-3 alkoxy, benzyloxy, pyridylC1-3alkoxy,thienylC1-3alkoxy, furanylC1-3alkoxy, C1-5 alkanoylamino, aroylamino,methylthio, benzylthio, C1-3 alkoxycarbonylamino, amino wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkylor phenyl, halogen, hydroxy, oxo, carboxy and cyano, R_(e) may befurther optionally substituted by one or more R_(f);

[0158] R_(f) is selected from the group consisting of C1-3 alkyl, phenyloptionally substituted by one or more groups selected from halogen andmethyl, C1-3 alkoxy, aryloxy, benzyloxy, C1-3 alkoxycarbonyl, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or phenyl, C1-5 alkanoylamino, aroylamino, amino wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkylor phenyl, halogen, hydroxy, oxo, carboxy and cyano;

[0159] or R6 and R7 together with the carbon they are attached formcyclopropyl or a heterocyclic ring selected from the group consisting ofpiperidinyl and pyranyl, the cyclopropyl or heterocyclic ring beingoptionally substituted with one or more R_(g).

[0160] R_(g) is methyl;

[0161] R_(h) is as described immediately above; and

[0162] X is O.

[0163] Yet even much more preferred are compounds of the formula (I) asdescribed immediately above and wherein:

[0164] A is as described above;

[0165] R1 is cyclopropyl, cyclohexyl, phenyl, naphthyl, piperidinyl,morpholinyl, piperazinyl, pyranyl, thiopyranyl or amino wherein R1 isoptionally substituted by one or more R_(a);

[0166] R_(a) is selected from the group consisting of C1-3 alkyl, C5-6cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, C1-3 alkoxy,C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or phenyl, C1-5alkanoylamino, aroylamino, C1-5 alkylsulfonylamino, arylsulfonylamino,amino wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl, halogen, hydroxy, oxo, carboxy and cyano,R_(a) may be further optionally substituted by one or more R_(b);

[0167] R_(b) is selected from the group consisting of C1-3 alkoxy,halogen and hydroxy,

[0168] R2, R3 and R4 are as described immediately above;

[0169] R5 is C1-5 alkyl or C5-6 cycloalkyl wherein R5 is optionallysubstituted by one or more R_(c);

[0170] R_(c) is selected from the group consisting of methyl, C3-6cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl,C1-4 alkoxy, C1-5 alkanoylamino, methylthio, halogen, hydroxy, oxo,carboxy and cyano, R_(c) may be further optionally substituted by one ormore R_(d);

[0171] R_(d) is selected from the group consisting of methyl, phenyl,benzyl, methoxy, phenoxy, benzyloxy, benzoyl, halogen and hydroxy;

[0172] R6 is as described immediately above;

[0173] R7 is C1-5 alkyl or phenyl, wherein R7 is optionally substitutedby one or more R_(e);

[0174] R_(e) is selected from the group consisting of C3-6 cycloalkyl,phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy,benzyloxy, C1-3 alkanoylamino, methylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, benzylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, methoxycarbonylamino, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, halogen, hydroxy, carboxy and cyano, R_(e) may be furtheroptionally substituted by one or more R_(f);

[0175] R_(f) is selected from the group consisting of methyl, phenyloptionally substituted by one or more groups selected from halogen ormethyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkylor phenyl, halogen, hydroxy and carboxy;

[0176] or R6 and R7 together with the carbon they are attached form acyclopropyl ring; and

[0177] R_(g), R_(h) and X are as described immediately above.

[0178] Ultimately preferred are compounds of the formula (I) asdescribed immediately above and wherein:

[0179] A is as described above;

[0180] R1 is cyclopropyl, cyclohexyl, phenyl, naphthyl, piperidinyl,morpholinyl, piperazinyl, pyranyl or thiopyranyl, wherein R1 isoptionally substituted by one or more R_(a);

[0181] R_(a) is selected from the group consisting of pyrrolyl,imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, halogen, hydroxy and carboxy, R_(a) may be furtheroptionally substituted by one or more R_(b);

[0182] R_(b) is selected from the group consisting of methoxy, halogenand hydroxy;

[0183] R2, R3,R4 and R5 are as described immediately above;

[0184] R_(c) is selected from the group consisting of methyl, C3-6cycloalkyl, phenyl, naphthyl, C1-4 alkoxy, C1-3 alkanoylamino,methylthio, halogen, hydroxy, oxo, carboxy and cyano, R_(c) may befurther optionally substituted by one or more R_(d);

[0185] R_(d) is selected from the group consisting of methyl, phenyl,methoxy, halogen and hydroxy;

[0186] R6 is hydrogen;

[0187] R7 is as described immediately above;

[0188] R_(e) is selected from the group consisting of C5-6 cycloalkyl,phenyl, naphthyl, thienyl, indolyl, methoxy, benzyloxy, methylthio,benzylthio, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano,R_(e) may be further optionally substituted by one or more R_(f);

[0189] R_(f) is selected from the group consisting of methyl, phenyloptionally substituted by halogen, methoxy, phenoxy, benzyloxy,methoxycarbonyl, halogen, hydroxy and carboxy; and

[0190] R_(g), R_(h) and X are as described immediately above.

[0191] Ultimately preferred are compounds of the formula (I) wherein:

[0192] A is as described above;

[0193] R1 is 4-morpholinyl, 4-pyranyl or phenyl;

[0194] R2, R3,R4, R_(a) and R_(b) are as described immediately above;

[0195] R5 is C1-5 alkyl wherein R5 is optionally substituted by one ormore R_(c);

[0196] R_(c) is selected from the group consisting of C3-6 cycloalkyl,phenyl and 2-naphthyl, R_(c) may be further optionally substituted byone or more R_(d);

[0197] R_(d) is selected from the group consisting of methyl andhalogen,

[0198] R6 and R7 are as described immediately above;

[0199] R_(e) is selected from the group consisting of C5-6 cycloalkyl,phenyl, naphthyl, indolyl, benzyloxy, methylthio, benzylthiohalogen andcarboxy, R_(e) may be further optionally substituted by one or moreR_(f); and

[0200] R_(f) is selected from the group consisting of methyl, methoxy,methoxycarbonyl, halogen and hydroxy; and

[0201] R_(g), R_(h) and X are as described immediately above.

[0202] In a second generic aspect of the invention, there are providedcompounds of formula (Ia):

[0203] wherein:

[0204] A is —C(O)— or —CH(OR8)—;

[0205] R1 is alkyl, alkoxy, cycloalkyl, aryl, aryloxy, benzyloxy,heterocyclyl, heteroaryl or amino wherein R1 is optionally substitutedby one or more Ra;

[0206] Ra is selected from the group consisting of a bond, alkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkanoyl,aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byalkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino,alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxideor sulfone, ureido wherein either nitrogen atom may be independentlysubstituted by alkyl, aryl, heterocyclyl or heteroaryl,alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy,arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl, heterocyclylor heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino; Ra may be further optionally substituted by one or more Rb;

[0207] R_(b) is selected from the group consisting of alkyl, cycloalkyl,aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy,alkanoyl, aroyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by alkyl, aryl, acyl, heterocyclyl or heteroaryl,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;

[0208] R2 is hydrogen, OR_(j) or lower alkyl;

[0209] R3 is hydrogen or lower alkyl;

[0210] R4 is hydrogen or lower alkyl;

[0211] R5 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl, wherein R5 is optionally substituted by one or more R_(c);

[0212] R_(c) is selected from the group consisting of a bond, alkyl,cycloalkyl, bicycloalkyl, aryl, indenyl, indanyl, dihydronaphthyl,tetrahydronaphthyl, heterocyclyl, heteroaryl, alkoxy, aryloxy,arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl,alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by alkyl, aryl, heterocyclyl orheteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by alkyl, aryl,heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino,alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino,arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino whereinthe nitrogen atom may be independently mono or di-substituted by alkyl,aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino, R_(c) may be further optionallysubstituted by one or more R_(d);

[0213] R_(d) is selected from the group consisting of alkyl, cycloalkyl,aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;

[0214] or R4 and R5 together with the carbon they are attached form a 3to 7 membered carbocyclic ring optionally substituted with one or moreR_(d);

[0215] R6 is hydrogen or lower alkyl wherein one or more carbon atomsare optionally replaced by 1 to two heteroatoms selected from the groupconsisting of N, O and S;

[0216] R7 is hydrogen, alkyl wherein one or more carbon atoms areoptionally replaced by 1 to two heteroatoms selected from the groupconsisting of N, O and S, cycloalkyl, aryl, heterocyclyl, heteroaryl orcyano, wherein R7 is optionally substituted by one or more R_(e);

[0217] R_(e) is selected from the group consisting of a bond alkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy,alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy,heteroarylalkoxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by alkyl, aryl, heterocyclyl orheteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl,alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxideor sulfone, arylalkylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by alkyl, aryl, heterocyclyl or heteroaryl,alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy,arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl, heterocyclylor heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino, R_(e) may be further optionally substituted by one or moreR_(f);

[0218] R_(f) is selected from the group consisting of alkyl, cycloalkyl,aryl optionally substituted by one or more groups selected from halogen,methyl or methoxy, heterocyclyl, heteroaryl, alkoxy, aryloxy,arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by alkyl, aryl, heterocyclyl or heteroaryl,alkanoylamino, aroylamino, -alkylcarbamoyl, arylcarbamoyl, alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by alkyl, aryl, heterocyclyl or heteroaryl,alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy,arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl, heterocyclylor heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino;

[0219] or R6 and R7 together with the carbon they are attached form a 3to 7 membered carbocyclic or heterocyclic ring, the carbocyclic orheterocyclic ring being optionally substituted with one or more R_(g);

[0220] R_(g) is selected from the group consisting of a bond, alkyl,cycloalkyl, bicycloalkyl, benzyl, aryl, dihydronaphthyl,tetrahydronaphthyl, indenyl, indanyl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, indolinyl andpiperazinyl, heteroaryl selected from the group consisting of furanyl,thienyl, pyrimidinyl, pyrrolyl, imidazolyl and pyridinyl, C1-5 alkanoyl,aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, carbamoyl wherein thenitrogen atom may be independantly mono or disubstituted by C1-5 alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl,pyridinyl, benzimidazolyl and quinolinyl, C1-5 alkanoylamino,aroylamino, C1-5 alkylthio, arylthio, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or disubstituted byalkyl, cycloalkyl, bicycloalkyl, aryl, aroyl, benzoyl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidinoand guanidino, R_(g) may be further optionally substituted by one ormore R_(h);

[0221] R_(h) is selected from the group consisting of a bond, C1-5alkyl, C3-7 cycloalkyl, aryl optionally substituted by one or moregroups selected from halogen, lower alkyl or lower alkoxy, benzyl,benzyloxy, dihydronaphthyl, tertrahydronaphthyl, indenyl, indanyl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,tetrahydropyranyl and tetrahydrothiopyranyl, heteroaryl selected fromthe group consisting of furanyl, thienyl pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl, benzoxazolyl and quinoxalinyl, C1-5 alkoxy, aryloxy, aminowherein the nitrogen atom may be independently mono or di-substituted byalkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl and morpholinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl and pyridinyl,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;R_(h) may be further optionally substituted by one or more R_(i);

[0222] R_(i) is alkyl, hydroxy, oxo and halogen;

[0223] R_(j) is hydrogen, alkyl, cycloalkyl;

[0224] R8 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or arylalkyl;

[0225] X is O or S; and

[0226] pharmaceutically acceptable salts, esters or tautomers thereof.

[0227] Preferred are compounds of the formula (Ia)

[0228] wherein:

[0229] R1 is C1-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selectedfrom the group consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, 2-oxo-5-aza-bicyclo[2,2,1]heptanyl, piperazinyl,indolinyl, tetrahydropyranyl and tetrahydrothiopyranyl, heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyland phenoxazinyl and amino wherein R1 is optionally substituted by oneor more R_(a);

[0230] R_(a) is selected from the group consisting of a bond, C1-8alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl, heteroaryl selected from the group consistingof furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, C1-8alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-8 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino,aroylamino, C1-8 alkylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidizedto a sulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy,arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino, guanidino; R_(a) may be further optionally substitutedby one or more R_(b);

[0231] R_(b) is selected from the group consisting of C1-8 alkyl, C3-6cycloalkyl, aryl, heteroaryl, C1-8 alkoxy, aryloxy, alkanoyl, aroyl,amino wherein the nitrogen atom may be independently mono ordi-substituted by alkyl, cycloalkyl, aryl, heterocyclyl selected fromthe group consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino;

[0232] R2 is hydrogen, OR_(j) or C1-3 alkyl;

[0233] R3 is hydrogen or C1-5 alkyl;

[0234] R4 is hydrogen or C1-5 alkyl;

[0235] R5 is hydrogen, C1-8 alkyl, C3-7 cycloalkyl, aryl wherein R5 isoptionally substituted by one or more R_(c);

[0236] R_(c) is selected from the group consisting of a bond, C1-8alkyl, C3-7 cycloalkyl, bicycloalkyl, aryl, dihydronaphthyl,tetrahydronaphthyl, indenyl, indanyl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,C1-8 alkoxy, aryloxy, alkanoyl, aroyl, C1-8 alkoxycarbonyl,aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-8 alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxideor sulfone, ureido wherein either nitrogen atom may be independentlysubstituted by alkyl, aryl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl, or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,alkoxycarbonylamino, C1-5aryloxycarbonylamino, alkylcarbamoyloxy,arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyland phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidinoand guanidino, R_(c) may be further optionally substituted by one ormore R_(d);

[0237] R_(d) is selected from the group consisting of C1-8 alkyl, C3-6cycloalkyl, aryl, arylalkyl, C1-8 alkoxy, aryloxy, arylalkoxy, aroyl,amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino;

[0238] R7 is hydrogen, C1-8 alkyl wherein one or more carbon atoms areoptionally replaced by 1 to two heteroatoms selected from the groupconsisting of N, O and S, C3-7 cycloalkyl, aryl, heteroaryl or cyano,wherein R7 is optionally substituted by one or more R_(e);

[0239] R_(e) is selected from the group consisting of a bond, C1-8alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl; heteroaryl selected from the group consistingof furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy,arylC1-8alkoxy, heteroarylC1-8alkoxy wherein the heteroaryl is ashereinabove described in this paragraph, C1-8 alkoxycarbonyl,aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-8 alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxideor sulfone, arylC1-8 alkylthio, ureido wherein either nitrogen atom maybe independently substituted by alkyl, aryl, heterocyclyl selected fromthe group consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy,arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyland phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidinoand guanidino, R_(e) may be further optionally substituted by one ormore R_(f);

[0240] R_(f) is selected from the group consisting C1-8 alkyl, C3-7cycloalkyl, aryl optionally substituted by one or more groups selectedfrom the group consisting halogen, methyl and methoxy, heterocyclylselected from the group consisting pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyland phenoxazinyl, C1-8 alkoxy, aryloxy, arylC1-8alkoxy, C1-8alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-8 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino,aroylamino, C1-8 alkylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidizedto a sulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy,arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyland phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino,and guanidino;

[0241] or R6 and R7 together with the carbon they are attached form a 3to 7 membered carbocyclic or heterocyclic ring, the carbocyclic orheterocyclic ring being optionally substituted with one or more R_(g);

[0242] R_(g) is selected from the group consisting of a bond, alkyl,cycloalkyl, bicycloalkyl, phenyl, naphthyl, benzyl, dihydronaphthyl,tetrahydronaphthyl, indenyl, indanyl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, indolinyl andpiperazinyl, heteroaryl selected from the group consisting of furanyl,thienyl, pyrimidinyl and pyridinyl, C1-5alkanoyl, aroyl,C1-5alkoxycarbonyl, aryloxycarbonyl, carbamoyl wherein the nitrogen atommay be independantly mono or disubstituted by C1-5 alkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl,pyridinyl, benzimidazolyl and quinolinyl, amino wherein the nitrogenatom may be independently mono or di-substituted by C1-5 alkyl, C3-6cycloalkyl, C7-8 bicycloalkyl, phenyl, benzyl, benzoyl or naphthoyl,C1-5 alkylthio wherein the sulfur atom may be oxidised to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidised to a sulfoxideor sulfone, C1-5 alkylaminosulfonyl, arylaminosulfonyl, halogen,hydroxy, oxo, carboxy and cyano, R_(g) may be further optionallysubstituted by one or more R_(h);

[0243] R_(h) is selected from the group consisting of C1-5 alkyl, C3-7cycloalkyl, aryl optionally substituted by one or more groups selectedfrom halogen, C1-5 alkyl or C1-5 alkoxy, dihydronaphthyl,tertrahydronaphthyl, indenyl, indanyl, benzyl, benzyloxy, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, tetrahydropyranyland tetrahydrothiopyranyl, heteroaryl selected from the group consistingof furanyl, thienyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl,quinazolinyl, benzoxazolyl and quinoxalinyl, C1-5 alkoxy, aryloxy, aminowherein the nitrogen atom may be independently mono or di-substituted byalkyl, aryl, heterocyclyl selected from the group consisting ofpiperidinyl and morpholinyl, or heteroaryl selected from the groupconsisting of furanyl, thienyl and pyridinyl, halogen, hydroxy, oxo,carboxy and cyano; and

[0244] R8 is hydrogen, alkyl, cycloalkyl-alkyl or arylalkyl;

[0245] R_(i) is C1-8 alkyl, hydroxy, oxo and halogen

[0246] R_(j) is hydrogen or alkyl and

[0247] X is O.

[0248] More preferred are compounds of the formula (I) as describedimmediately above and wherein:

[0249] A is —C(O)—;

[0250] R1 is C1-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, 2-oxa-5-aza-bicyclo[2,2,1]heptanyl,piperazinyl, tetrahydropyranyl and tetrahydrothiopyranyl; heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl or amino, wherein R1 is optionally substituted by one ormore R_(a);

[0251] R_(a) is selected from the group consisting of a bond, C1-3alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl andpiperazinyl; heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl,pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl and isoquinolinyl, C1-3 alkoxy, phenoxy, C1-3alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, phenyl or heteroaryl selected from the group consisting offuranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl and isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5alkylthio, arylthio, ureido wherein either nitrogen atom may beindependently substituted by C1-5alkyl, phenyl or naphthyl; C1-5alkoxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-5alkyl, phenyl, naphthyl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl andpiperazinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyland isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, R_(a) maybe further optionally substituted by one or more R_(b);

[0252] R_(b) is selected from the group consisting of C1-3 alkyl, C5-6cycloalkyl, aryl, heteroaryl selected from the group consisting offuranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl and isoquinolinyl, C1-3 alkoxy, phenoxy, C1-8 alkanoyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5alkyl, C3-6 cycloalkyl, phenyl or naphthyl, halogen, hydroxy, oxo,carboxy and cyano;

[0253] R2 is hydrogen;

[0254] R3 is hydrogen;

[0255] R4 is hydrogen;

[0256] R5 is C1-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R5 isoptionally substituted by one or more R_(c);

[0257] R_(c) is selected from the group consisting of a bond, C1-3alkyl, C3-6 cycloalkyl, phenyl, naphthyl, indenyl, indanyl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl andpiperazinyl, heteroaryl selected from the group consisting of furanyl,thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, quinolinyl andisoquinolinyl, C1-5 alkoxy, phenoxy, aroyl, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,phenyl, naphthyl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl and indolyl, C1-5 alkanoylamino, aroylamino, C1-3alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, phenylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by C1-3 alkyl, phenyl or heteroaryl selectedthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl and indolyl, C1-5 alkoxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-3 alkyl, phenyl, heterocyclyl selected fromthe group consisting of piperidinyl, morpholinyl and piperazinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl,halogen, hydroxy, oxo, carboxy and cyano, R_(c) may be furtheroptionally substituted by one or more R_(d);

[0258] R_(d) is selected from the group consisting of C1-5 alkyl, C5-6cycloalkyl, phenyl, naphthyl, arylC1-3alkyl, C1-5 alkoxy, phenoxy,arylC1-3alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano;

[0259] R6 is hydrogen or C1-3alkyl wherein one or more carbon atoms areoptionally replaced by 1 to two heteroatoms selected from the groupconsisting of N, O and S;

[0260] R7 is hydrogen, C1-5 alkyl wherein one or more carbon atoms areoptionally replaced by 1 to two heteroatoms selected from the groupconsisting of N, O and S, C3-6 cycloalkyl, phenyl, naphthyl, heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl or cyano, wherein R7 is optionally substituted by one ormore R_(e);

[0261] R_(e) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl;heteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyland isoquinolinyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy,heteroarylC1-3alkoxy wherein the heteroaryl is as hereinabove describedin this paragraph, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, phenyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5alkanoylamino, aroylamino, C1-3 alkylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, arylC1-3alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by C1-5 alkyl orphenyl, C1-5 alkoxycarbonylamino, C1-5 alkylsulfonylamino,arylsulfonylamino, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl andpiperazinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and pyridinyl,indolyl, halogen, hydroxy, oxo, carboxy and cyano, R_(e) may be furtheroptionally substituted by one or more R_(f);

[0262] R_(f) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, phenyl optionally substituted by one or more groups selectedfrom halogen or methyl, heterocyclyl selected from the group consistingof pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl andindolyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkylor aryl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-5alkyl or aryl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl or aryl, halogen, hydroxy, oxo, carboxy and cyano; or

[0263] R6 and R7 together with the carbon they are attached form acarbocyclic ring selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or heterocyclic ringselected from the group consisting of azetidinyl, pyrrolidinyl,piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl, thecarbocyclic or heterocyclic ring being optionally substituted with oneor more R_(g);

[0264] R_(g) is selected from the group consisting of a bond, C1-8alkyl, C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl, dihydronaphthyl,tetrahydronaphthyl, indenyl, indanyl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperazinyl and morpholinyl, heteroaryl selectedfrom the group consisting of thienyl, pyrimidinyl and pyridinyl, C1-5alkanoyl, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom maybe independantly mono or disubstituted by C1-5 alkyl and amino whereinthe nitrogen atom may be independently mono or di-substituted by C1-5alkyl, C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, benzyl, benzoyl ornaphthoyl, R_(g) may be further optionally substituted by one or moreR_(h); and

[0265] R_(h) is selected from the group consisting of C1-8 alkyl, C3-8cycloalkyl, phenyl, benzyl, benzyloxy, heterocyclyl selected from thegroup consisting of piperidinyl, indolinyl, tetrahydropyranyl andtetrahydrothiopyranyl, heteroaryl selected from the group consisting ofthienyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, benzimidazolyl,quinolinyl and isoquinolinyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl, halogen, hydroxy,oxo, cyano and trifluoromethyl.

[0266] Even more preferred are compounds of the formula (Ia) asdescribed immediately above and wherein:

[0267] R1 is C3-6 cycloalkyl, phenyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydropyranyl, furanyl, thienyl, pyrrolyl or amino, wherein R1 isoptionally substituted by one or more R_(a);

[0268] R_(a) is selected from the group consisting of a bond, C1-3alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, C1-3alkoxy, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or phenyl;C1-5alkoxycarbonylamino, C1-5 alkanoylamino, aroylamino, ureido whereineither nitrogen atom may be independently substituted by C1-3alkyl orphenyl;, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein thenitrogen atom may be independently mono or di-substituted by C1-3alkylor phenyl, halogen, hydroxy, oxo, carboxy and cyano, R_(a) may befurther optionally substituted by one or more R_(b);

[0269] R_(b) is selected from the group consisting of C1-3alkyl,C1-3alkoxy, amino wherein the nitrogen atom may be independently mono ordi-substituted by C1-3alkyl or phenyl halogen, oxo and hydroxy;

[0270] R5 is C1-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R5 isoptionally substituted by one or more groups of the formula R_(c);

[0271] R_(c) is selected from the group consisting of a bond, C1-3alkyl, C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, naphthyl,dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, 4-piperidinyl,furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, C1-3alkoxy, C1-5 alkoxycarbonyl, C1-5 alkanoyloxy, benzoyloxy, 20-carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or phenyl, C1-5 alkanoylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, C1-3alkoxycarbonylamino, C1-3 alkylsulfonylamino, amino wherein the nitrogenatom may be independently mono or di-substituted by C1-3 alkyl orphenyl, halogen, hydroxy, oxo, carboxy and cyano, R_(c) may be furtheroptionally substituted by one or more R_(d);

[0272] R_(d) is selected from the group consisting of C1-3 alkyl,phenyl, benzyl, C1-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen,hydroxy, oxo, carboxy and cyano;

[0273] wherein the configuration at the stereocenter defined by R4 andR5 and the carbon they are attached to is defined as L;

[0274] R6 is hydrogen or C1-2alkyl one or more carbon atoms areoptionally replaced by 1 to two heteroatoms selected from the groupconsisting of N, O and S;

[0275] R7 is C1-5 alkyl said alkyl being optionally interrupted by 1 totwo heteroatoms selected from the group consisting of N, O and S;phenyl, pyridinyl or cyano wherein R7 is optionally substituted by oneor more groups of the formula R_(e);

[0276] R_(e) is selected from the group consisting of a bond, methyl,C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl,imidazolyl, pyridinyl, pyrrolidinyl, piperidinyl, indolyl, C1-3 alkoxy,benzyloxy, pyridinylC1-3alkoxy, thienylC1-3 alkoxy, furanylC1-3alkoxy,C1-5 alkanoylamino, aroylamino, methylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, benzylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, C1-3alkoxycarbonylamino, amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl or phenyl, halogen,hydroxy, oxo, carboxy and cyano, R_(e) may be further optionallysubstituted by one or more R_(f);

[0277] R_(f) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, phenyl optionally substituted by one or more groups selectedfrom halogen or methyl, C1-3 alkoxy, aryloxy, benzyloxy, C1-3alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by C1-3 alkyl or phenyl, C1-5 alkanoylamino,aroylamino, amino wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxyand cyano;

[0278] R6 and R7 together with the carbon they are attached form acarbocyclic ring selected from the group consisting of cyclopropyl,cyclopentyl, cyclohexyl and cycloheptyl or heterocyclic ring selectedfrom the group consisting of pyrrolidinyl, piperidinyl andtetrahydropyranyl, the carbocyclic or heterocyclic ring being optionallysubstituted with one or more R_(g);

[0279] R_(g) is selected from the group consisting of a bond C1-8 alkyl,C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl, dihydronaphthyl,tetrahydronaphthyl, indanyl, heterocyclyl selected from the groupconsisting of piperidinyl, tetrahydropyranyl, and tetrahydrothiopyranyl,C1-5 alkanoyl, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atommay be independantly mono or disubstituted by C1-5 alkyl and aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, benzyl, benzoylor naphthoyl, R_(g) may be further optionally substituted by one or moreR_(h); and

[0280] R_(h) is selected from the group consisting of C1-8 alkyl, C3-8cycloalkyl, phenyl, benzyl, benzyloxy, heterocyclyl selected from thegroup consisting of piperidinyl, indolinyl, tetrahydropyranyl andtetrahydrothiopyranyl, heteroaryl selected from the group consisting ofthienyl, pyridinyl, indolyl, pyrrolyl and benzimidazolyl, amino whereinthe nitrogen atom may be independently mono or di-substituted by methyl,halogen, hydroxy, oxo, cyano and trifluoromethyl.

[0281] Yet even more preferred are compounds of the formula (Ia) asdescribed immediately above and wherein:

[0282] R1 is cyclohexyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, or amino wherein R1 is optionallysubstituted by one or more R_(a);

[0283] R_(a) is selected from the group consisting of a bond, C1-3alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, C1-3alkoxy, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or phenyl,C1-5alkoxycarbonylamino, C1-5 alkanoylamino, aroylamino, C1-5alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3 alkyl, halogen,hydroxy, oxo, carboxy and cyano, R_(a) may be further optionallysubstituted by one or more R_(b);

[0284] R_(b) is selected from the group consisting of C1-3 alkoxy,halogen and hydroxy,

[0285] R5 is C1-5 alkyl wherein R5 is optionally substituted by one ormore R_(c);

[0286] R_(c) is selected from the group consisting of a bond, C3-6cycloalkyl, C7-8 bicycloalkyl, phenyl, naphthyl, dihydronaphthyl,tetrahydronaphthyl, indanyl, thienyl, imidazolyl, pyridinyl, indolyl,C1-3 alkoxy, C1-5 alkanoylamino, methylthio, halogen, hydroxy, oxo,carboxy and cyano, R_(c) may be further optionally substituted by one ormore R_(d);

[0287] R_(d) is selected from the group consisting of C1-3 alkyl,phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl, halogen andhydroxy;

[0288] R7 is C1-5 alkyl or phenyl, wherein R7 is optionally substitutedby one or more R_(e);

[0289] R_(e) is selected from the group consisting of a bond, C3-6cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyrrolidinyl,piperidinyl, pyridinyl, indolyl, C1-5 alkoxy, benzyloxy, C1-3alkanoylamino, methylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, benzylthio wherein the sulfur atom may be oxidizedto a sulfoxide or sulfone, methoxycarbonylamino, amino wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,halogen, hydroxy, carboxy and cyano, R_(e) may be further optionallysubstituted by one or more R_(f);

[0290] R_(f) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, phenyl optionally substituted by one or more groups selectedfrom halogen or methyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl,amino wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl or phenyl, halogen, hydroxy and carboxy;

[0291] R6 and R7 together with the carbon they are attached form acarbocyclic ring selected from the group consisting of cyclopropyl andcyclohexyl or heterocyclic ring selected from the group consisting ofpyrrolidinyl and piperidinyl, the carbocyclic or heterocyclic ring beingoptionally substituted with one or more R_(g);

[0292] R_(g) is selected from the group consisting of a bond, C1-8alkyl, C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl, tetrahydronaphthyl,indanyl, heterocyclyl selected from the group consisting oftetrahydropyranyl and tetrahydrothiopyranyl, acetyl, methoxycarbonyl,carbamoyl wherein the nitrogen atom may be independantly mono ordisubstituted by C1-3 alkyl and amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, C3-6 cycloalkyl,benzyl or benzoyl, R_(g) may be farther optionally substituted by one ormore R_(h); and

[0293] R_(h) is selected from the group consisting of C1-8 alkyl, C3-7cycloalkyl, phenyl, benzyl, benzyloxy, heterocyclyl selected from thegroup consisting of piperidinyl, tetrahydropyranyl andtetrahydrothiopyranyl, heteroaryl selected from the group consisting ofthienyl, pyridinyl, indolyl and benzimidazolyl, amino, methylamino,dimethylamino, halogen, hydroxy, oxo, cyano and trifluoromethyl.

[0294] Still yet even more preferred are compounds of the formula (I) asdescribed immediately above and wherein:

[0295] R1 is phenyl, naphthyl, pyrrolidinyl, thiomorpholinyl ormorpholinyl, wherein R1 is optionally substituted by one or more R_(a);

[0296] R_(a) is selected from the group consisting of a bond, C1-3alkyl, pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy,methoxycarbonyl, t-butoxycarbonylamino, C1-3 alkylsulfonylamino, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, halogen, hydroxy, cyano and carboxy, R_(a) may be furtheroptionally substituted by one or more R_(b);

[0297] R_(b) is selected from the group consisting of methoxy, halogenand hydroxy;

[0298] R_(c) is selected from the group consisting of a bond, methyl,C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, naphthyl,tetrahydronaphthyl, indanyl, C1-4 alkoxy, C1-3 alkanoylamino,methylthio, halogen, hydroxy, oxo, carboxy and cyano, R_(c) may befurther optionally substituted by one or more R_(d);

[0299] R_(d) is selected from the group consisting of C1-3 alkyl,phenyl, methoxy, halogen and hydroxy;

[0300] R6 is hydrogen;

[0301] R_(e) is selected from the group consisting of a bond, C5-6cycloalkyl, phenyl, C1-5 alkoxy, C1-5 alkylamino, pyrrolidinyl,piperidinyl, naphthyl, thienyl, indolyl, methoxy, benzyloxy, methylthio,benzylthio, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano,R_(e) may be further optionally substituted by one or more R_(f); and

[0302] R_(f) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, phenyl optionally substituted by halogen, methoxy, phenoxy,benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy.

[0303] R6 and R7 together with the carbon they are attached form acyclopropyl ring or heterocyclic ring selected from the group consistingof pyrrolidinyl and piperidinyl, the cyclopropyl or heterocyclic ringbeing optionally substituted with one or more R_(g);

[0304] R_(g) is selected from the group consisting of a bond, C1-8alkyl, C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl, α-tetrahydronaphthyl,α-indanyl, tetrahydropyranyl, tetrahydrothiopyranyl and amino whereinthe nitrogen atom may be independently mono or di-substituted by C1-5alkyl, C3-6 cycloalkyl, benzyl or benzoyl, R_(g) may be furtheroptionally substituted by one or more R_(h); and

[0305] R_(h) is selected from the group consisting of C1-5 alkyl, C3-7cycloalkyl, phenyl, benzyl, benzyloxy, tetrahydropyranyl, heteroarylselected from the group consisting of thienyl, pyridinyl, indolyl,pyrrolyl and benzimidazolyl, halogen, hydroxy, oxo, cyano ortrifluoromethyl, may be further substituted by R_(i); and

[0306] R_(i) is C1-8 alkyl and halogen.

[0307] Even much more preferred are compounds of the formula (la) asdescribed immediately above and wherein:

[0308] R1 is phenyl, morpholinyl, thiomorpholinyl or pyrrolidinyl, R1 isoptionally substituted by one or more R_(a);

[0309] R_(a) is selected from the group consisting of C1-3 alkyl,methoxy, C1-3 alkylsulfonylamino, halogen, hydroxy, cyano andtrifluoromethyl;

[0310] R5 is C1-3 alkyl wherein R5 is optionally substituted by one ormore R_(c);

[0311] R_(c) is selected from the group consisting of C3-6 cycloalkyl,C7-8 bicycloalkyl, phenyl, naphthyl, β-tetrahydronaphthyl or β-indanyl,R_(c) may be further optionally substituted by one or more R_(d);

[0312] R_(d) is selected from the group consisting of methyl, methoxyand halogen;

[0313] R7 is C1-5 alkyl wherein R7 is optionally substituted by one ormore R_(e);

[0314] R_(e) is selected from the group consisting of phenyl, naphthyl,C1-5 alkoxy, C1-5 alkylamino, pyrrolidinyl and piperidinyl, R_(e) may befurther optionally substituted by one or more R_(f); and

[0315] R_(f) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, phenyl optionally substituted with halogen, halogen andhydroxy.

[0316] or R6 and R7 together with the carbon they are attached form acyclopropyl ring or heterocyclic ring selected from the group consistingof piperidinyl and pyrrolidinyl, the cyclopropyl or heterocyclic ringbeing optionally substituted with one or more R_(g); and

[0317] R_(g) is selected from the group consisting of C1-8 alkyl, C3-8cycloalkyl, C7-8 bicycloalkyl, benzyl, α-tetrahydronaphthyl, α-indanyl,tetrahydropyranyl, tetrahydrothiopyranyl and amino group wherein thenitrogen atom may be independantly mono or disubstuituted by C1-5 alkylor C3-6 cycloalkyl,; R_(g) may be further optionally substituted by oneor more R_(h); and

[0318] R_(h) is selected from the group consisting of C1-5 alkyl, C3-7cycloalkyl, phenyl, benzyl, benzyloxy, thienyl, pyrrolyl, indolyl,pyridinyl, halogen, hydroxy, cyano and trifluoromethyl; R_(h) may befurther optionally substituted by one or more R_(i); and

[0319] R_(i) is C1-5 alkyl and halogen.

[0320] Yet even much more preferred are compounds of the formula (Ia) asdescribed immediately above and wherein:

[0321] R1 is 4-morpholinyl or pyrrolidinyl, wherein R1 is optionallysubstituted by one or more R_(a);

[0322] R_(a) is C1-3 alkylsulfonylamino;

[0323] R5 is C1-3 alkyl wherein R5 is optionally substituted by one ormore R_(c);

[0324] R_(c) is selected from the group consisting of C5-6 cycloalkyl,C7-8 bicycloalkyl, β-tetrahydronaphthyl and β-indanyl, R_(c) may befurther optionally substituted by one or more R_(d);

[0325] R_(d) is selected from the group consisting of methyl, methoxyand halogen;

[0326] R7 is C1-5 alkyl wherein R7 is optionally substituted by one ormore R_(e);

[0327] R_(e) is selected from the group consisting of C1-5 alkoxy, C1-5alkylamino, pyrrolidinyl and piperidinyl, R_(e) may be furtheroptionally substituted by one or more R_(f); and

[0328] R_(f) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, phenyl optionally substituted with halogen, halogen andhydroxy.

[0329] or R6 and R7 together with the carbon they are attached formheterocyclic ring selected from the group consisting of piperidinyl andpyrrolidinyl, the heterocyclic ring being optionally substituted withone or more R_(g); and

[0330] R_(g) is selected from the group consisting of C1-8 alkyl, C3-8cycloalkyl, C7-8 bicycloalkyl, benzyl, α-tetrahydronaphthyl, α-indanyl,tetrahydropyranyl and tetrahydrothiopyranyl; R_(g) may be furtheroptionally substituted by one or more R_(h); and

[0331] R_(h) is selected from the group consisting of C1-5 alkyl, C3-7cycloalkyl, phenyl, pyridinyl, indolyl, thienyl, halogen, hydroxy, cyanoand trifluoromethyl; R_(h) may be further optionally substituted by oneor more R_(i);

[0332] R_(i) is selected from the group consisting of C1-3 alkyl andhalogen.

[0333] Ultimately preferred are compounds of the formula (Ia) asdescribed immediately above and wherein:

[0334] R1 is 4-morpholinyl;

[0335] R5 is C1-3 alkyl wherein R5 is optionally substituted by one ormore R_(c);

[0336] R_(c) is selected from the group consisting of cyclohexyl,β-tetrahydronaphthyl and β-indanyl, R_(c) may be further optionallysubstituted by one or more R_(d);

[0337] R_(d) is selected from the group consisting of methyl andhalogen;

[0338] R7 is C1-5 alkyl wherein R7 is optionally substituted by one ormore R_(e);

[0339] R_(e) is selected from the group consisting of C1-2alkoxy andC1-2 alkylamino, R_(e) may be further optionally substituted by one ormore R_(f);

[0340] R_(f) is selected from the group consisting of C1-3 alkyl,phenyl, halogen and hydroxy;

[0341] or R6 and R7 together with the carbon they are attached form aheterocyclic ring selected from the group consisting of piperidinyl andpyrrolidinyl, the heterocyclic ring being optionally substituted withone or more R_(g); and

[0342] R_(g) is selected from the group consisting of C1-5 alkyl, C3-8cycloalkyl, C7-8 bicycloalkyl, benzyl and α-tetrahydronaphthyl; R_(g)may be further optionally substituted by one or more R_(h); and

[0343] R_(h) is C1-5 alkyl, C3-7 cycloalkyl, thienyl, pyridinyl,indolyl, halogen, hydroxy and trifluoromethyl; R_(h) may be furtheroptionally substituted by one or more Ri;

[0344] Ri is methyl.

[0345] The activity of particular compounds disclosed herein againstcathepsin K may be determined without undue experimentation by one ofordinary skill in the art in view of the art, the guidance providedthroughout this specification and by the art recognized methods referredto in the section entitled “Assessment of Biological Properties.”

[0346] The following subgeneric aspect of the compounds of the formula(Ia) is postulated to possess Cathepsin K activity:

[0347] The broadest embodiment of the formula (Ia) as describedhereinabove and wherein

[0348] A is —C(O)—;

[0349] R1 is aryl or aryloxy wherein R1 is optionally substituted by oneor more Ra;

[0350] R2 is hydrogen;

[0351] R3 is hydrogen;

[0352] R4 is hydrogen or lower alkyl;

[0353] R5 is alkyl optionally substituted by one or more R_(c);

[0354] or R4 and R5 together with the carbon they are attached form a 3to 7 membered carbocyclic ring optionally substituted with one or moreR_(d);

[0355] R6 is hydrogen or lower alkyl wherein one or more carbon atomsare optionally replaced by 1 to two heteroatoms selected from the groupconsisting of N, O and S;

[0356] R7 is hydrogen, alkyl wherein one or more carbon atoms areoptionally replaced by 1 to two heteroatoms selected from the groupconsisting of N, O and S, cycloalkyl, aryl, heterocyclyl, heteroaryl orcyano, wherein R7 is optionally substituted by one or more R_(e);

[0357] R6 and R7 together with the carbon they are attached form acarbocyclic ring selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or heterocyclic ringselected from the group consisting of azetidinyl, pyrrolidinyl,piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl, thecarbocyclic or heterocyclic ring being optionally substituted with oneor more R_(g);

[0358] Preferred cathepsin K inhibitors are those as describedimmediately above and wherein:

[0359] R1 is naphthyl, benzyloxy or phenoxy wherein R1 is optionallysubstituted by one or more Ra;

[0360] R4 is hydrogen or lower alkyl;

[0361] R5 is lower alkyl optionally substituted by one or more R_(c);

[0362] or R4 and R5 together with the carbon they are attached form a 5to 6 membered carbocyclic ring optionally substituted with one or moreR_(d);

[0363] R6 is hydrogen or lower alkyl wherein one or more carbon atomsare optionally replaced by N;

[0364] R7 is lower alkyl wherein one or more carbon atoms are optionallyreplaced by heteroatoms selected from the group consisting of N and 0,R7 is optionally substituted by one or more R_(e);

[0365] R6 and R7 together with the carbon they are attached form aheterocyclic ring selected from the group consisting of pyrrolidinyl andpiperidinyl each being optionally substituted with one or more R_(g).

[0366] Most preferred cathepsin K inhibitors are those as describedimmediately above and wherein:

[0367] R4 is hydrogen or lower alkyl;

[0368] R5 is C1-4 alkyl optionally substituted by one or more R_(c);

[0369] or R4 and R5 together with the carbon they are attached form acyclohexyl ring optionally substituted with one or more R_(d);

[0370] R7 is lower alkyl wherein one or more carbon atoms are optionallyreplaced by heteroatoms selected from the group consisting of N and O orbenzyloxy;

[0371] R6 and R7 together with the carbon they are attached formpyrrolidinyl optionally substituted with one or more R_(g).

[0372] The following are representative compounds of the invention:

[0373] 4-Methyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(2-benzyloxy-1-cyano-ethyl)-amide. MS: m/z=402 M+1;

[0374]N-(Benzyloxymethyl-cyano-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0375]N-(1-Cyano-3-phenyl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=426 M+1;

[0376] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(2-benzyloxy-1-cyano-ethyl)-amide. MS: m/z=416 M+1;

[0377] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(1-cyano-3-phenyl-propyl)-amide. MS: m/z=400 M+1;

[0378] 2-(Morpholine-4-carbonyl)-cyclohexanecarboxylic acid(benzyloxymethyl-cyano-methyl)-amide;

[0379]N-(2-Benzyloxy-1-cyano-ethyl)-4-morpholin-4-yl-2-naphthalen-2-ylmethyl-4-oxo-butyramide.MS: m/z=486 M+1;

[0380]N-[2-(4-Chloro-benzyloxy)-1-cyano-ethyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=477 M+1;

[0381]N¹-(Benzyloxymethyl-cyano-methyl)-N⁴-[4-(5-chloro-H-benzoimidazol-2-yl)-phenyl]-2-cyclohexylmethyl-succinamide;

[0382]N⁴-[2-(4-Acetylamino-phenyl)-N¹-(2-benzyloxy)-1-cyano-ethyl]-2-cyclohexylmethyl-succinamide.MS: m/z=505 M+1;

[0383]N-(cyano-1-methyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0384]N-(cyano-cyclopropyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0385]N-(cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0386] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide. MS: m/z=407 M+1;

[0387] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(1-benzyl-4-cyano-piperidin-4-yl)-amide. MS: m/z=455 M+1;

[0388]N-(1-Benzyl-4-cyano-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=481 M+1;

[0389]N-[1-(3-Benzyloxy-benzyl)-3-cyano-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=573 M+1;

[0390]N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1;

[0391]N-[3-Cyano-1-(2,6-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=503 M+1;

[0392]N-[3-Cyano-1-(3,5-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z 503 M+1;

[0393]N-[3-Cyano-1-(3-trifluoromethyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=535 M+1;

[0394]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=459 M+1;

[0395]4,4-Dimethyl-2-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=460 M+1;

[0396] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=447 M+1;

[0397] 4,4-Dimethyl-2-(2-oxo-2-piperidin-1-yl-ethyl)-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=445 M+1;

[0398] 4,4-Dimethyl-2-(2-oxo-2-thiomorpholin-4-yl-ethyl)-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=463 M+1;

[0399]N-(3-cyano-1-(3,3-dimethyl-butyl)-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0400]N-(3-Cyano-1-isopropyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=419 M+1;

[0401]N-(3-Cyano-1-methyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z 391 M+1;

[0402]N-[3-Cyano-1-(-ethyl-propyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=447 M+1;

[0403]N-(3-Cyano-1-isobutyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=433 M+1;

[0404]N-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=431 M+1;

[0405]N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=481 M+1;

[0406]N-(3-Cyano-1-methyl-piperidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=405 M+1;

[0407]N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-y]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1;

[0408]N-(3-Cyano-1-propyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=419 M+1;

[0409]N-(3-Cyano-1-cyclopentyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=445 M+1;

[0410]N-(1-cyano-3-piperidin-1-yl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0411](4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(1-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;

[0412]N-[1-Cyano-3-(cyclohexyl-ethyl-amino)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z 475 M+1;

[0413]N-[3-(Benzyl-isopropyl-amino)-1-cyano-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=497 M+1;

[0414]N-[3-Cyano-1-(1H-indol-2-ylmethyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0415]N⁴-Carbamoylmethyl-N¹-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-N-methyl-succinamide;

[0416]N-(3-Cyano-1-cycloheptyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1;

[0417]N-[3-Cyano-1-(1,2,3,4-tetrahydro-naphthalen-1-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=507 M+1;

[0418]N-(1-Bicyclo[2.2.1]hept-2-yl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=471 M+1;

[0419]N-(4-Cyano-1-propyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=433 M+1;

[0420]N-(1-Benzyl-4-cyano-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=487 M+1;

[0421]N-[3-Cyano-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 461=M+1;

[0422]N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 477=M+1;

[0423]N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 477=M+1;

[0424]N-[3-Cyano-1-(2-phenyl-benzyl)-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 543=M+1;

[0425]N-[3-Cyano-1-(3-phenyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 543=M+1;

[0426]N-{1-[(benzyl-methyl-amino)-methyl]-1-cyano-3-phenyl-propyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0427]N-(4-Cyano-1,2-dimethyl-piperidin-4-yl)-2-cycloheyxlmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0428](4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;

[0429]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(trans-4-phenyl-cyclohexylmethyl)-butyramide;

[0430]2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-butyramide;

[0431]2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(4-cyano-1-methyl-piperidin-4-yl)-4-morpholin-4-yl-4-oxo-butyramide;

[0432]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-butyramide;MS, m/z 507=M+1;

[0433]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-indan-2-ylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 493=M+1;

[0434]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclopentylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 445=M+1;

[0435][2-Cyano-2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-ethyl]-carbamicacid tert-butyl ester;

[0436]N-{Cyano-[(cyclohexyl-ethyl-amino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0437]N-{Cyano-[(dibenzylamino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0438]N-{[(Benzyl-ethyl-amino)-methyl]-cyano-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0439]N-(Cyano-piperidin-1-ylmethyl-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0440] {1-[3-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-4-cyclohexyl-butyryl]-pyrrolidin-3-yl}-carbamic acidtert-butyl ester. MS: m/z=566.5 M+1;

[0441] {1-[3-(3-Cyano-1-cyclohexyl -pyrrolidin-3-ylcarbamoyl)-4-cyclohexyl-butyryl]-pyrrolidin-3-yl}-carbamic acidtert-butyl ester. MS: m/z=558.6 M+1;

[0442]N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-dimethylamino-pyrrolidin-1-yl)-4-oxo-butyramide.MS: m/z=494.5 M+1;

[0443]N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)-4-oxo-butyramide.MS: m/z=544.4 M+1;

[0444]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)-4-oxo-butyramide.MS: m/z=536.4 M+1;

[0445]N-[(3S)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0446]N-[(3R)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0447]N-[(3S)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0448]N-[(3R)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0449]N-[(3S)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0450]N-[(3R)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0451]N-[(3S)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0452]N-[(3R)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0453]N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0454]N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3R)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0455]N-[1-cis-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0456]N-[1-cis-(4-tert-Butyl-cyclohexyl)-(3R)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0457]N-[(3S)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0458]N-[(3R)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0459]N-[(3S)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0460]N-[(3R)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0461]N-[(3S)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0462]N-[(3R)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0463]N-[(3S)-3-Cyano-1-cis-(3-isopropylcyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0464]N-[(3R)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0465]N-[(3S)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0466]N-[(3R)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0467]N-[(3S)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0468]N-[(3R)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0469]N-[(3S)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0470]N-[(3R)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0471]N-[(3S)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0472]N-[(3R)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0473]N-[(3S)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-yl-4-oxo-butyramide;

[0474]N-[(3R)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0475]N-[(3S)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0476]N-[(3R)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0477]N-[(3S)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0478]N-[(3R)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0479]N-[(3S)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0480]N-[(3R)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0481]N-[(S)-Cyano-methyl-phenyl-methyl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0482]N-[(R)-Cyano-methyl-phenyl-methyl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0483]N-[(S)-Cyano-methyl-pyridin-4-yl-methyl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0484]N-[(R)-Cyano-methyl-pyridin-4-yl-methyl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0485]N-[(3S)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0486]N-[(3R)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0487]N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0488]N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0489]N-[(3S)-3-Cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0490]N-[(3R)-3-Cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramideand

[0491] the pharmaceutically acceptable salts, esters or tautomersthereof.

[0492] Of the aforementioned compounds, preferred are the following:

[0493] 4-Methyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(2-benzyloxy-1-cyano-ethyl)-amide. MS: m/z=402 M+1;

[0494]N-(Benzyloxymethyl-cyano-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0495]N-(1-Cyano-3-phenyl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=426 M+1;

[0496] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(2-benzyloxy-1-cyano-ethyl)-amide. MS: m/z=416 M+1;

[0497] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(1-cyano-3-phenyl-propyl)-amide. MS: m/z=400 M+1;

[0498]N-(2-Benzyloxy-1-cyano-ethyl)-4-morpholin-4-yl-2-naphthalen-2-ylmethyl-4-oxo-butyramide.MS: m/z=486 M+1;

[0499]N-[2-(4-Chloro-benzyloxy)-1-cyano-ethyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=477 M+1;

[0500]N-(cyano-1-methyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0501]N-(cyano-cyclopropyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0502]N-(cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0503]N-(1-Benzyl-4-cyano-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=481 M+1;

[0504]N-[1-(3-Benzyloxy-benzyl)-3-cyano-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=573 M+1;

[0505]N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1;

[0506]N-[3-Cyano-1-(2,6-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=503 M+1;

[0507]N-[3-Cyano-1-(3,5-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=503 M+1;

[0508]N-[3-Cyano-1-(3-trifluoromethyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=535 M+1;

[0509]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=459 M+1;

[0510] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=447 M+1;

[0511] 4,4-Dimethyl-2-(2-oxo-2-thiomorpholin-4-yl-ethyl)-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=463 M+1;

[0512]N-(3-cyano-1-(3,3-dimethyl-butyl)-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0513]N-(3-Cyano-1-isopropyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=419 M+1;

[0514]N-(3-Cyano-1-methyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=391 M+1;

[0515]N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=447 M+1;

[0516]N-(3-Cyano-1-isobutyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=433 M+1;

[0517]N-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=431 M+1;

[0518]N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=481 M+1;

[0519]N-(3-Cyano-1-methyl-piperidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=405 M+1;

[0520]N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1;

[0521]N-(3-Cyano-1-propyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=419 M+1;

[0522]N-(3-Cyano-1-cyclopentyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=445 M+1;

[0523](4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(1-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;

[0524]N-[1-Cyano-3-(cyclohexyl-ethyl-amino)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=475 M+1;

[0525]N-[3-(Benzyl-isopropyl-amino)-1-cyano-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=497 M+1;

[0526]N-[3-Cyano-1-(1H-indol-2-ylmethyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0527]N⁴-Carbamoylmethyl-N¹-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-N⁴-methyl-succinamide;

[0528]N-(3-Cyano-1-cycloheptyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1;

[0529]N-[3-Cyano-1-(1,2,3,4-tetrahydro-naphthalen-1-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=507 M+1;

[0530]N-(1-Bicyclo[2.2.1]hept-2-yl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=471 M+1;

[0531]N-(4-Cyano-1-propyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=433 M+1;

[0532]N-(1-Benzyl-4-cyano-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=487 M+1;

[0533]N-[3-Cyano-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 461=M+1;

[0534]N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 477=M+1;

[0535]N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 477=M+1;

[0536]N-[3-Cyano-1-(2-phenyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 543=M+1;

[0537]N-[3-Cyano-1-(3-phenyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 543=M+1;

[0538](4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;

[0539]2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-butyramide;

[0540]2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(4-cyano-1-methyl-piperidin-4-yl)-4-morpholin-4-yl-4-oxo-butyramide;

[0541]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-butyramide;MS, m/z 507=M+1;

[0542]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-indan-2-ylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 493=M+1;

[0543]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclopentylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 445=M+1;

[0544][2-Cyano-2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-ethyl]-carbamicacid tert-butyl ester;

[0545]N-{Cyano-[(cyclohexyl-ethyl-amino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0546]N-{Cyano-[(dibenzylamino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0547]N-{[(Benzyl-ethyl-amino)-methyl]-cyano-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0548]N-(Cyano-piperidin-1-ylmethyl-methyl)-2-cyclohexylmethyl-4-morpholin-41-4-oxo-butyramide;

[0549] {1-[3-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-4-cyclohexyl-butyryl]-pyrrolidin-3-yl}-carbamic acidtert-butyl ester. MS: m/z=566.5 M+1;

[0550] {1-[3-(3-Cyano-1-cyclohexyl -pyrrolidin-3-ylcarbamoyl)-4-cyclohexyl-butyryl]-pyrrolidin-3-yl}-carbamic acidtert-butyl ester. MS: m/z=558.6 M+1;

[0551]N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-dimethylamino-pyrrolidin-1-yl)-4-oxo-butyramide.MS: m/z=494.5 M+1;

[0552]N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)-4-oxo-butyramide.MS: m/z=544.4 M+1;

[0553]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)-4-oxo-butyramide.MS: m/z=536.4 M+1;

[0554]N-[(3S)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0555]N-[(3R)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0556]N-[(3S)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0557]N-[(3R)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0558]N-[(3S)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0559]N-[(3R)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0560]N-[(3S)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0561]N-[(3R)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0562]N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0563]N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3R)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0564]N-[1-cis-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0565]N-[1-cis-(4-tert-Butyl-cyclohexyl)-(3R)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0566]N-[(3S)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0567]N-[(3R)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0568]N-[(3S)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0569]N-[(3R)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0570]N-[(3S)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0571]N-[(3R)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0572]N-[(3S)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0573]N-[(3R)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0574]N-[(3S)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0575]N-[(3R)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0576]N-[(3S)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0577]N-[(3R)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0578]N-[(3S)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0579]N-[(3R)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0580]N-[(3S)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0581]N-[(3R)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0582]N-[(3S)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0583]N-[(3R)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0584]N-[(3S)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0585]N-[(3R)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0586]N-[(3S)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0587]N-[(3R)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0588]N-[(3S)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0589]N-[(3R)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0590]N-[(3S)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0591]N-[(3R)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0592]N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0593]N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0594]N-[(3S)-3-Cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramideand

[0595]N-[(3R)-3-Cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.

[0596] Of the above-listed preferred compounds, the following are morepreferred compounds of the invention:

[0597]N-(Benzyloxymethyl-cyano-methyl)-2-cyclohexylmethyl-4-morpholin-⁴-yl-⁴-oxo-butyramide;

[0598]N-[2-(4-Chloro-benzyloxy)-1-cyano-ethyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=477 M+1;

[0599]N-(cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0600]N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1;

[0601]N-[3-Cyano-1-(2,6-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=503 M+1;

[0602]N-[3-Cyano-1-(3,5-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: i/z=503 M+1;

[0603]N-[3-Cyano-1-(3-trifluoromethyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=535 M+1;

[0604]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=459 M+1;

[0605]N-(3-cyano-1-(3,3-dimethyl-butyl)-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0606]N-(3-Cyano-1-isopropyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=419 M+1;

[0607]N-(3-Cyano-1-isobutyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=433 M+1;

[0608]N-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=431 M+1;

[0609]N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z=481 M+1;

[0610]N-(3-Cyano-1-methyl-piperidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=405 M+1;

[0611]N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1;

[0612]N-(3-Cyano-1-propyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=419 M+1;

[0613]N-(3-Cyano-1-cyclopentyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=445 M+1;

[0614]N-[3-Cyano-1-(1H-indol-2-ylmethyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0615]N-(3-Cyano-1-cycloheptyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1;

[0616]N-[3-Cyano-1-(1,2,3,4-tetrahydro-naphthalen-1-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=507 M+1;

[0617]N-(1-Bicyclo[2.2.1]hept-2-yl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=471 M+1;

[0618]N-[3-Cyano-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-14-morpholin-4-yl-4-oxo-butyramide,MS: m/z 461=M+1;

[0619]N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 477=M+1;

[0620]N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 477=M+1;

[0621](4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;

[0622]2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-butyramide;

[0623]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-butyramide;MS, m/z 507=M+1;

[0624]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-indan-2-ylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 493=M+1;

[0625]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclopentylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 445=M+1;

[0626]N-{Cyano-[(cyclohexyl-ethyl-amino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0627]N-(Cyano-piperidin-1-ylmethyl-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0628]N-[(3S)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0629]N-[(3S)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0630]N-[(3S)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0631]N-[(3S)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0632]N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0633]N-[(3S)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0634]N-[(3S)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0635]N-[(3R)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0636] cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0637]N-[(3R)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0638]N-[(3S)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0639]N-[(3S)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0640]N-[(3R)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0641]N-[(3S)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0642]N-[(3S)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0643]N-[(3S)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0644]N-[(3S)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0645]N-[(3S)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0646]N-[(3S)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0647]N-[(3S)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0648]N-[(3R)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0649]N-[(3S)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramideand

[0650]N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.

[0651] Of the above-listed more preferred compounds, the following aremost preferred compounds of the invention:

[0652]N-(cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0653]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=459 M+1;

[0654]N-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z -431 M+1;

[0655]N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=481 M+1;

[0656]N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1;

[0657](4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;

[0658]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-butyramide;MS, m/z 507=M+1;

[0659]N-[(3S)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0660]N-[(3S)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;

[0661]N-[(3R)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramideand

[0662]N-[(3S)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.

[0663] Any compounds of this invention containing one or more asymmetriccarbon atoms may occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. Each stereogenic carbon may be in the R or Sconfiguration, or a combination of configurations.

[0664] Some of the compounds of formulas (I) and (Ia) can exist in morethan one tautomeric form. The invention includes all such tautomers.

[0665] It shall be understood by one of ordinary skill in the art thatall compounds of the invention are those which are chemically stable.

[0666] The invention includes pharmaceutically acceptable derivatives ofcompounds of formulas (I) and (Ia). A “pharmaceutically acceptablederivative” refers to any pharmaceutically acceptable salt or ester of acompound of this invention, or any other compound which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound of this invention, a pharmacologically activemetabolite or pharmacologically active residue thereof.

[0667] In addition, the compounds of this invention include prodrugs ofcompounds of the formulas (I) and (Ia). Prodrugs include those compoundsthat, upon simple chemical transformation, are modified to produce thecompounds of the invention. Simple chemical transformations includehydrolysis, oxidation and reduction. Specifically, when a prodrug ofthis invention is administered to a patient, the prodrug may betransformed into a compound of formula (I) and (Ia), thereby impartingthe desired pharmacological effect.

[0668] In order that the invention herein described may be more fullyunderstood, the following detailed description is set forth. As usedherein, the following abbreviations are used:

[0669] BOC or t-BOC is tertiary butoxycarbonyl

[0670] t-Bu is tertiary butyl

[0671] DMF is dimethylformamide

[0672] EtOAc is ethyl acetate

[0673] THF is tetrahydrofuran

[0674] Ar is argon

[0675] EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride

[0676] HOBT is 1-hydroxybenzotriazole.

[0677] Also, as used herein, each of the following terms, used alone orin conjunction with other terms, are defined as follows (except wherenoted to the contrary):

[0678] The term “alkyl” refers to a saturated aliphatic radicalcontaining from one to ten carbon atoms or a mono- or polyunsaturatedaliphatic hydrocarbon radical containing from two to twelve carbonatoms, containing at least one double or triple bond, respectively.“Alkyl” refers to both branched and unbranched alkyl groups. Preferredalkyl groups are straight chain alkyl groups containing from one toeight carbon atoms and branched alkyl groups containing from three toeight carbon atoms. More preferred alkyl groups are straight chain alkylgroups containing from one to six carbon atoms and branched alkyl groupscontaining from three to six carbon atoms. It should be understood thatany combination term using an “alk” or “alkyl” prefix refers to analogsaccording to the above definition of “alkyl”. For example, terms such as“alkoxy”, “alkythio” refer to alkyl groups linked to a second group viaan oxygen or sulfur atom. “Alkanoyl refers to an alkyl group linked to acarbonyl group (C═O).

[0679] The term “cycloalkyl” refers to the cyclic analog of an alkylgroup, as defined above, optionally unsaturated and substituted.Preferred cycloalkyl groups are saturated cycloalkyl groups containingfrom three to eight carbon atoms, and more preferably three to sixcarbon atoms.

[0680] The term “aryl” refers to phenyl and naphthyl.

[0681] Each of the above defined “alkyl”, “cycloalkyl” and “aryl” shallbe understood to include their halogenated analogs.

[0682] The term “halo” refers to a halogen radical selected from fluoro,chloro, bromo or iodo. Preferred halo groups are fluoro, chloro andbromo.

[0683] The term “heteroaryl” refers to a stable 5-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicaromatic heterocycle radical. Each heterocycle consists of carbon atomsand from 1 to 4 heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. The heterocycle may be attached by any atomof the cycle, which results in the creation of a stable structure.Preferred heteroaryl radicals include, for example, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl,benzthiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl or phenoxazinyl,

[0684] The term “heterocycle” refers to a stable 5-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicheterocycle radical which may be either saturated or unsaturated, and isnon-aromatic. Each heterocycle consists of carbon atoms and from 1 to 4heteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. The heterocycle may be attached by any atom of the cycle, whichresults in the creation of a stable structure. Preferred heterocycleradicals include, for example, pyrrolinyl, pyrrolidinyl, pyrazolinyl,pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl,thiopyranyl, piperazinyl, indolinyl, azetidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl,hexahydropyridazinyl, 1,4,5,6-tetrahydropyrimidin-2-ylamine,dihydro-oxazolyl, 1,2-thiazinanyl-1,1-dioxide,1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide andimidazolidinyl-2,4-dione.

[0685] The terms “heterocycle”, “heteroaryl” or “aryl”, when associatedwith another moiety, unless otherwise specified shall have the samemeaning as given above. For example, “aroyl” refers to phenyl ornaphthyl linked to a carbonyl group (C═O).

[0686] Each aryl or heteroaryl unless otherwise specified includes it'spartially or fully hydrogenated derivative. For example, quinolinyl mayinclude decahydroquinolinyl and tetrahydroquinolinyl, naphthyl mayinclude it's hydrogenated derivatives such as tetrahydranaphthyl. Otherpartially or fully hydrogenated derivatives of the aryl and heteroarylcompounds described herein will be apparent to one of ordinary skill inthe art.

[0687] As used herein above and throughout this application, “nitrogen”and “sulfur” include any oxidized form of nitrogen and sulfur and thequatemized form of any basic nitrogen.

[0688] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustrating preferred embodiments of this invention, and are not to beconstrued as limiting the scope of the invention in any way.

[0689] The examples which follow are illustrative and, as recognized byone skilled in the art, particular reagents or conditions could bemodified as needed for individual compounds. Starting materials used inthe scheme below are either commercially available or easily preparedfrom commercially available materials by those skilled in the art.

GENERAL SYNTHETIC METHODS

[0690] The invention also provides processes of making the present novelcompounds. Compounds of the invention may be prepared by methodsdescribed below. Standard peptide coupling, protection and deprotectionreactions (see for example M. Bodanszky, The Practice of PeptideSynthesis, Springer-Verlag, 1984) are employed in these syntheses.Alkylated succinic acid derivatives used as starting materials areeither commercially available or easily prepared by methods known tothose skilled in the art. For example succinate derivatives may bealkylated by treatment with a suitable alkylating agent such as an alkylhalide in the presence of a suitable base such as lithium diisopropylamide. If the succinate derivative contains a chiral auxiliary, forexample a succinic acid chiral oxazolidine amide, a chiral alkylatedsuccinate derivative can be obtained as described by Azam et al. (J.Chem. Soc. Perkin Trans. 1, 1996, 621) and Evans et al. (J. Am. Chem.Soc., 1981, 103, 2127). Alternatively, racemic alkylated succinatederivatives may be resolved by methods known to those skilled in the artif desired, for example by selective enzymatic hydrolysis as describedby Oikawa et al. (Tetrahedron Lett., 1996, 37, 6169), Wirz et al.(Tetrahedron Asymmetry, 1997, 8, 187) and Ozaki et al. (Chem. Lett.,1997, 741).

[0691] Compounds of the invention in which R₁ is an amino group or aheterocyclyl group containing a nitrogen that forms an amide bond with A(A═—C(O)—) of formula I may be prepared as described below andillustrated in Scheme I.

[0692] A succinic acid monoester, for example a methyl ester as shown,is reacted with the desired amine R₁H under standard peptide couplingconditions. An example of standard coupling conditions would becombining the starting materials in the presence of a coupling reagentsuch as 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (EDC) with1-hydroxybenzotriazole (HOBT), in a suitable solvent such as DMF ormethylene chloride. A base such as N-methylmorpholine may be added. Theresulting amide ester is hydrolyzed in aqueous base or acid. A suitableco-solvent such as THF or MeOH may be added. The resulting acid is thencoupled with an amino nitrile under standard peptide coupling conditionsas described above to provide the desired compound of formula (I).Alternately, one may couple the acid with an amino amide and then reactthe resulting amide with a suitable dehydrating agent such as cyanuricchloride in a suitable solvent such as DMF to provide the desirednitrile of formula (I).

[0693] Compounds of the invention in which R₁ is alkyl or cycloalkyl maybe prepared by reacting a succinic acid ester derivative, for example amethyl ester as shown below, containing an activated amide, for examplea N-methoxy-N-methylamide (Solladic-Cavallo et al., TetrahedronAsymmetry, 1996, 7, 1797), or a N-imidazolium-N-methylamide (De LasHeras et al., Tetrahedron Lett., 1997, 38, 1817) with a suitableorganometallic reagent, such as an alkylmagnesium bromide (Scheme II).The resulting ketoester is then carried forth as described for the amideester intermediate in Scheme I.

[0694] Compounds of the invention in which R1 is aryl or heteroaryl maybe prepared by reacting a suitable aryl or heteroaryl organometallicreagent with an activated amide as described above for R₁=alkyl orcycloalkyl. In addition, an acyl halide, for example an acid chloride,may be used in place of an activated amide. Suitable aryl or heteroarylorganometallic reagents for reaction with acyl halides are known in theart and include aryl magnesium bromides (F. Babudri et al., Tetrahedron,1996, 52, 13513), aryl lithium reagents in the presence of ZnCl₂ (C. Kimet al., Tetrahedron Lett., 1994, 35, 3017) and aryl stannanes under Pdcatalyzed Stille coupling conditions (M. J. Plunkett et al., J. Am.Chem. Soc., 1995, 117, 3306).

[0695] A method which may be used to stereoselectively prepare alkylatedsuccinic acid derivatives, useful in the procedures described in SchemesI and II, is illustrated in Scheme III.

[0696] In this procedure, a carboxylic acid bearing R₄ and R₅ is coupledwith a chiral auxiliary group known in the art (see for example D. Evanset al., J. Am. Chem. Soc., 1990, 401 1; D. Evans et al., J. Am. Chem.Soc., 1981, 2127, 103; D. Evans et al., Tetrahedron Lett, 1987, 6141; D.Evans et al., Tetrahedron Lett, 1987, 1123), such as(S)-(-)-4-isopropyl-2-oxazolidinone as illustrated in Scheme III.Suitable coupling conditions would include first converting thecarboxylic acid to an acid chloride, for example by reaction with oxalylchloride and DMF in a suitable solvent such as methylene chloride atabout 0° C. to room temperature. The acid chloride may then be coupledto the oxazolidinone in a suitable solvent, such as THF, in the presenceof a suitable base, such as n-BuLi at about −78° C. to room temperature.

[0697] The resulting product is then alkylated with a halomethylcarbonylcompound bearing R₁, R₂ and R₃ in a suitable solvent such as THF, in thepresence of a suitable base, such as sodium bis(trimethylsilyl)amide atabout −78° C. to room temperature. The large group on the chiralauxiliary (the isopropyl group in the illustrated example) directs thealkylating group to the side opposite it providing predominantly oneisomer at the alkylated carbon. The chiral auxiliary is then removed bymethods known in the art, for example in the case illustrated, in asuitable solvent such as THF in the presence of water and a suitableperoxide such as 30% hydrogen peroxide at about 0° C., providing thedesired succinic acid derivative which may be used in the procedureoutlined in Scheme I, or converted to the corresponding ester by methodsknown to those skilled in the art and used in the procedure outlined inScheme II.

[0698] Compounds of the invention in which R1 is alkyl, cycloalkyl, arylor heteroaryl and A is —C(O)— may be reacted with a suitable reducingagent such as sodium borohydride to produce the corresponding compoundwhere A is —C(OH)—

[0699] The synthetic examples below are illustrative of the methods usedto prepare the compounds of the invention.

SYNTHETIC EXAMPLES Example 1

[0700]N-(Benzyloxymethyl-cyano-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0701] (a) (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric Acid1-methyl Ester

[0702] (R)-2-(Cyclohexylmethyl) succinic acid 1-methyl ester (1.00 g,4.38 mmol) was dissolved in 10 mL of DMF and cooled to 0° C. with anice-water bath. EDC (1.12 g, 5.69 mmol) then 1-hydroxybenzotriazole(0.77 g, 5.69 mmol) were added and stirring continued, under argon, for25 min. Morpholine (0.76 mL, 8.76 mmol) was added and stirring wascontinued overnight (16 h). The solution was diluted with 200 mL ofEtOAc and washed with a 1.0 M solution of HCl (3×100 mL), a saturatedsolution of NaHCO₃ (3×100 mL), water (100 mL), then with brine (100 mL).The organic layer was dried over MgSO₄, filtered and concentrated byrotary evaporation to give(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid 1-methylester (1.26 g, 99%) as a white solid. The product was used in thefollowing step without purification.

[0703] (b) (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric Acid

[0704] The ester from the above step (1.21 g, 4.06 mmol) was dissolvedin THF (55 mL) and MeOH (27 mL) was then added. This solution was cooledto 0° C. with an ice-water bath, then a solution of LiOH.H₂O (0.51 g,12.18 mmol) in H₂O (27 mL) was slowly added and the mixture was allowedto stir for 5 hr at room temperature. The mixture was poured into water(100 mL) and extracted with Et₂O (2×50 mL). The aqueous layer wasacidified with 1.0 N HCl, then extracted with EtOAc (3×50 mL). Thecombined organic layers were then washed with H₂O (2×50 mL) followed bybrine (2×50 mL), dried over Na₂SO₄, filtered and the solvent wasevaporated to afford(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (0.88 g, 76%)as a clean white solid that was used without further purification.

[0705] (c) N-(t-butoxycarbonyl)-L-(O-benzyl)serinamide

[0706] NH₄OH (10 mL) was added to a premixed (15 min) solution ofN-(t-butoxycarbonyl)-L-(O-benzyl)serine (10.0 g, 33.9 mmol), EDC (7.80g, 40.7 mmol), and HOBT (5.50 g, 40.7 mmol) in DMF (120 mL) at roomtemperature. After 16 h the reaction mixture was diluted with CH₂Cl₂ andfiltered, washed sequentially with 10% aq. HCl, satd. NaHCO₃, H₂O (×3),brine, then dried over Na₂SO₄, and concentrated givingN-(t-butoxycarbonyl)-L-(O-benzyl)serinamide (1.5 g) as a white solid.

[0707] (d) L-(O-Benzyl) Serine Amide HCl

[0708] N-(t-butoxycarbonyl)-L-(O-benzyl)serinamide (1.00 g) wasdissolved in anhydrous THF (5 ml) and cooled in an ice/water bath. A 4Msolution of HCl in dioxane (5 ml) was added and the reaction stirred fortwo h and then concentrated under reduced pressure to provide a glasswhich was then triturated with diethyl ether to obtain L-(O-Benzyl)Serine amide HCl as a white solid (0.9 g). This material was usedwithout further purification.

[0709] (e)N-(2-Benzyloxy-1-carbamoyl-ethyl)-2-cyclohexylmethyl-4-morpholin-4-yl-oxo-butyramide

[0710] (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (0.20g, 0.71 mmol) was dissolved in 6 mL of DMF and cooled to 0° C. with anice-water bath. EDC (0.18 g, 0.92 mmol) and 1-hydroxybenzotriazole (0.12g, 0.92 mmol) were added and stirring, under argon, continued for 25min. To the cold solution was added the HCl salt of0-benzyl-L-serineamide (0.16 g, 0.71 mmol), followed by addition ofN-methylmorpholine (0.23 mL, 2.10 mmol) and stirring was continuedovernight (16 h). The solution was diluted with 100 mL of EtOAc andwashed with a 1.0 M solution of HCl (3×10 mL), a saturated solution ofNaHCO₃ (3×10 mL), water (100 mL) then with brine (100 mL). The organiclayer was dried over MgSO₄, filtered and concentrated by rotaryevaporation to give (0.34 g, 106%) of the crude product which waschromatographed (SiO₂, 2% MeOH in EtOAc) to giveN-(2-Benzyloxy-1-carbamoyl-ethyl)-2-cyclohexylmethyl-4-morpholin-4-yl-oxo-butyramide(0.22 g, 69%).

[0711] (f)N-(Benzyloxymethyl-cyano-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0712]N-(2-Benzyloxy-1-carbamoyl-ethyl)-2-cyclohexylmethyl-4-morpholin-4-yl-oxo-butyramide(0.22 g, 0.48 mmol) was dissolved in 4 mL of DMF and cooled to 0° C.with an ice-water bath. To this solution was added cyanuric chloride(0.089 g, 0.48 mmol) and the reaction mixture was stirred for one h. Thereaction was quenched with cold water (2 mL), extracted with EtOAc(3×100 mL), and the organic layers were combined and washed with 100 mLbrine. The organic layer was dried over MgSO₄, filtered and concentratedby rotary evaporation to give the crude residue. The residue waspurified by chromatography (SiO₂, 35% hexane in EtOAc) to give the titlecompound as a clear oil (0.12 g, 57%); ¹H NMR (CDCl₃) 7.35 (5H, m),7.02-7.08 (1H, m), 5.01-5.09 (1H, m), 4.52-4.63 (2H, m), 3.72-3.34 (10H,m), 2.96-2.83 (1H, m), 2.78-2.62 (1H, m), 2.18-2.30 (1H, m), 1.75-1.51(6H, m), 1.30-1.07 (5H, m), 0.95-0.73 (2H, m). MS: m/z=442 M+1.

Example 2

[0713] 2-(Morpholine-4-carbonyl)-cyclohexanecarboxylic Acid(benzyloxymethyl-cyano-methyl)-amide

[0714] (a) 2-(Morpholine-4-carbonyl)-cyclohexanecarboxylic Acid

[0715] To a solution of cis-1,2-cyclohexane dicarboxylic anhydride (1.0g, 6.49 mmol) in CH₂Cl₂ (16 mL) was added morpholine (0.56 g, 6.49 mmol)at 0° C., the resulting mixture was allowed to stir at room temperatureovernight (20 h). When complete the reaction mixture was washed with HCl(1.0 N, 20 mL) then with H₂O (2×20 mL). The combined aqueous layers wereextracted with CH₂Cl₂ (3×10 mL), and the combined organic layers weredried over MgSO₄, the solvent was evaporated in vacuo to give the titlecompound (1.4 g, 90%) as a white solid which was used later withoutfurther purification.

[0716] (b) 2-(Morpholine-4-carbonyl)-cyclohexanecarboxylic Acid(2-benzyloxy-1-carbamoyl-ethyl)-amide

[0717] This compound was prepared by the procedure described in Example1 part e) from 2-(Morpholine-4-carbonyl)-cyclohexanecarboxylic acid andthe HCl salt of O-benzyl-L-serineamide to give the crude product whichwas chromatographed (SiO₂, 10% Hexanes in EtOAc) to yield the titlecompound (1.2 g, 50% yield).

[0718] (c) 2-(Morpholine-4-carbonyl)-cyclohexanecarboxylic Acid(benzyloxymethyl-cyano-ethyl)-amide

[0719] The amide from the step above (0.10 g, 0.24 mmol) and cyanuricchloride (0.044 g, 0.24 mmol) were reacted as described by the procedurein Example 1 part (f). The residue was purified by chromatography (SiO₂,50% Hexanes in EtOAc) to give the title compound as a clear oil (0.055g, 60%); ¹H NMR (CDCl₃) 7.38-7.1 (6H, m), 5.0 (1H, m), 4.6 (2H, m),3.75-3.36 (9H, m), 3.3-3.05 (1H, m), 2.55-2.3 (2H, m), 2.0-1.15 (8H, m).MS: m/z=400 M+1.

Example 3

[0720]N¹-(Benzyloxymethyl-cyano-methyl)-N⁴-[4-(5-chloro-H-benzoimidazol-2-yl)-phenyl]-2-cyclohexylmethyl-succinamide

[0721] (a) (5-Chloro-2-(4-nitro-phenyl)-1H-benzoimidazole

[0722] To a solution of 4-Nitrobenzaldehyde (6.4 g, 42.35 mmol) in THF(300 mL) was added 4-Chloro-1,2-phenylenediamine (4.0 g, 28.05 mmol),and the mixture was stirred under air at room temperature for two days.When complete the reaction mixture was diluted with EtOAc (200 mL),washed with H₂O (200 mL) then with HCl (1.0 N. 200 mL). The productprecipitated out and was collected by filtration under suction. Thesolid was washed with EtOAc and allowed to dry. The product wascollected as a brownish solid (4.2 g, 55%), pure HCl salt.

[0723] (b) 4-(5-Chloro-1H-benzoimidazol-2-yl)-phenylamine

[0724] In 500 mL round bottom flask was suspended5-Chloro-2-(4-nitro-phenyl)-1H-benzoimidazole (4.23 g, 13.66 mmol) inAcOH (30 mL) at 0° C., and to the suspension was added dropwiseSnCl₂.H₂O (9.4 g, 41.66 mmol), in HCl (15 mL). After the addition, theice bath was removed and the mixture was allowed to stir at roomtemperature overnight (16 h). The mixture was poured onto ice, and NaOH(50% aq.) was slowly added to pH 12. Then the mixture was extracted withEtOAc (4×150 mL). The combined organic layers were washed with brine,dried over NaSO₄ and filtered, the solvent was evaporated to yield theproduct as an orange oil. The oil was dissolved in EtOAc and washed withHCl (1.0 N, 100 mL) and the product was isolated as HCl salt (2.13 g,67%).

[0725] (c)N-[4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-2-cyclohexylmethyl-succinamicacid methyl Ester

[0726] This compound was prepared by the procedure described in Example1 part (a) from 4-(5-Chloro-1H-benzoimidazol-2-yl)-phenylamine and(R)-2-(Cyclohexylmethyl) succinic acid 1-methyl ester to give the crudeproduct (2.0 g, 51%), which was used in the next step without furtherpurification.

[0727] (d)N-14-(5-Chloro-1H-benzomidazol-2-yl)-phenyl]-2-cyclohexylmethyl-succinamicacid

[0728] This compound was prepared by the procedure described in Example1 part (b) fromN-[4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-2-cyclohexylmethyl-succinamicacid methyl ester, and was isolated as an HCl salt.

[0729] (e)N¹-(2-Benzyloxy-1-carbamoyl-ethyl)-N⁴-[4-(5-chloro-1R-benzoimidazol-2-yl)-phenyl]-2-cyclohexylmethyl-succinamide

[0730] This compound was prepared by the procedure described in Example1 part (e) fromN-[4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-2-cyclohexylmethyl-succinamicacid and the HCl salt of O-benzyl-L-serineamide to give the crudeproduct which was chromatographed (SiO₂, 30% hexanes in EtOAc) to yieldthe title compound in 76% yield.

[0731] (f)N¹-(Benzyloxymethyl-cyano-methyl)-N⁴-[4-(5-chloro-H-benzoimidazol-2-yl)-phenyl]-2-cyclohexylmethyl-succinamide

[0732] The amide from the step above (0.08 g, 0.13 mmol) and cyanuricchloride (0.024 g, 0.13 mmol) were reacted as described by the procedurein Example 1 part (f). The residue was purified by chromatography (SiO₂,35% MeOH in CH₂Cl₂) to give the title compound as two separateddiastereomers (0.05 g, 64%); ¹H NMR (CDCl₃) 8.2-7.92 (2H, m), 7.8-7.72(2H, m), 7.57-7.44 (2H, m), 7.3-7.15 (6H, m), 5.47 (1H, m), 4.5-4.4 (2H,m), 3.65-3.5 (2H, m), 3.1-3.0 (1H, m), 2.67-2.54 (1H, m), 2.47-2.34 (1H,m), 1.95-1.5 (7H, m), 1.4-1.15 (6H, m), 1.0-0.8 (3H, m). MS: m/z=599M+1.

Example 4

[0733]N-(Cyano-cyclopropyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0734] (a) 1-Amino-1-cyclopropanecarboxamide HCl

[0735] This compound was prepared by the procedures described in Example1 part (c and d) from 1-tert-Butoxycarbonylamino-cyclopropanecarboxylicacid.

[0736] (b)1-(2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-cyclopropanecarboxylicAcid Amide

[0737]1-(2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-cyclopropanecarboxylicacid amide was prepared by the procedure described in Example 1 part (e)from (R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (0.20 g,0.71 mmol), EDC (0.18 g, 0.92 mmol), 1-hydroxybenzotriazole (0.12 g,0.92 mmol) and the HCl salt of 1-amino-1-cyclopropanecarboxamide (0.096g, 0.71 mmol) to yield a white solid (0.084, 33%) after purification bypreparative HPLC.

[0738] (c)N-(Cyano-cyclopropyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0739] The amide from the step above (0.084 g, 0.23 mmol) and cyanuricchloride (0.042 g, 0.23 mmol) were reacted as described by the procedurein Example 1 part (f). The residue was purified by chromatography (SiO₂,2% MeOH in CH₂Cl₂) to give the title compound as a clear oil (0.03 g,38%); ¹H NMR (CDCl₃) 7.38 (1H, m), 3.75-3.36 (8H, m), 2.85-2.68 (2H, m),2.26-2.17 (1H, m), 1.74-1.53 (6H, m), 1.52-1.40 (2H), 1.27-1.02 (7H, m),0.90-0.74 (2H, m). MS: m/z=348 M+1.

Example 5

[0740]N-(Cyano-1-methyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4:yl-4-oxo-butyramide

[0741] (a) 4-Amino-4-cyano-1-methylpiperidine

[0742] A solution of ammonium chloride (1.89 g, 35.37 mmol) andpotassium cyanide (2.30 g, 35.37 mmol) was prepared in 50 mL of water.1-Methyl-4-piperidone (1 g, 8.84 mmol) was added to the solution andstirring was continued for 2 days. The solution was brought to pH 11with solid sodium carbonate and the reaction solution was extracted with3×100 mL of EtOAc. The organic layer was dried over Na₂SO₄, decanted andconcentrated to an orange oil (857 mg). ¹H NMR showed that the oil was a2:1:1 mixture of 4-amino-4-cyano-1-methylpiperidine, the correspondingcyanohydrin and starting ketone. The crude mixture was used in the nextstep without further purification.

[0743] (b)N-(Cyano-1-methyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0744] (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (0.20g, 0.71 mmol) (see Example 1-part a and b) was dissolved in 5 mL of DMFand cooled to 0° C. by an ice-water bath. EDC (0.18 g, 0.92 mmol) and1-hydroxybenzotriazole (0.12 g, 0.92 mmol) were added and stirring,under argon, continued for 25 min. Then4-amino-4-cyano-1-methylpiperidine (0.098 g, of the mixture ofaminonitrile:cyanohydrin:ketone) was dissolved in 1 mL of DMF and addedto the -solution of the active ester. The resulting mixture was stirredat ambient temperature for 4 h. The volatiles were removed in vacuo andthe resulting residue was dissolved in 100 mL of EtOAc and washedsequentially with 2×100 mL of saturated sodium bicarbonate and 1×100 mLof brine. The organic layer was dried over MgSO₄, filtered, andconcentrated to a thick oil. The oil was purified by columnchromatography on SiO₂ using as eluent 5% MeOH in CH₂Cl₂ to give thetitle compound as a clear oil (0.005 g): ¹H NMR (CDCl₃) 6.64 (1H, m),3.73-3.37 (8H, m), 2.95-2.85 (1H, m), 2.75-2.55 (2H, m), 2.5-2.37 (2H,m), 2.34-2.25 (3H, m), 1.98-1.82 (2H, m), 1.80-1.58 (6H, m), 1.32-1.10(8H, m), 0.95-0.78 (3H,m). MS: m/z=405 M+1.

Example 6

[0745]N-(Cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4yl-4-oxo-butyramide

[0746] (a) 3-Amino-3-cyano-1-benzylpyrrolidine

[0747] 3-Amino-3-cyano-1-benzylpyrrolidine was prepared by a methodanalogous to that of Example 5-part (a) with the exception that nosodium carbonate was added to the reaction mixture. The product wasextracted from the crude reaction with 3×100 mL of EtOAc and was usedwithout purification.

[0748] (b)N-(Cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.Separated diastereomers

[0749] DiastereomericN-(cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramidewas prepared by a method analogous to that of Example 3-part (d). Thepurification was done by reverse phase preparative HPLC to separate thetwo diastereomers. ¹H NMR (CDCl₃) 7.31 (5H, m), 6.81 (1H, s), 3.66-3.47(1OH, m), 3.21-3.18 (1H, m), 2.85-2.67 (5H, m), 2.3-2.1 (3H, m),1.72-1.65 (5H, m), 1.25-1.16 (5H, m), 0.95-0.78 (3H,m). MS, m/Z 467=M+1.

Example 7

[0750]N-(3-Cyano-1-(33-dimethyl-butyl)-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0751] (a) 1-(3,3-Dimethyl-butyl)-pyrrolidin-3-ol

[0752] Acetic acid (31 μL), pyrrolidin-3-ol (3.47 g, 39.8 mmol) and3,3-dimethyl-butyraldehyde (3.99 g, 39.8 mmol) were dissolved in THF(100 mL) and stirred at room temperature for 40 min. The solution wasthen cooled to 0° C. on an ice bath. To the cold solution sodiumtriacetoxyborohydride (10.98 g, 51.8 mmol) was added and the mixture wasstirred at room temperature overnight. The reaction mixture was basifiedwith a 5.0 M solution of NaOH and extracted with CH₂Cl₂ (3×1 50 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated todryness to afford 1-(3,3-dimethyl-butyl)-pyrrolidin-3-ol in (6.34 g,92.5%), which was used without purification.

[0753] (b) 1-(3,3-Dimethyl-butyl)-pyrrolidin-3-one

[0754] To a dry 500 mL round bottom flask was added oxalyl chloride(9.40 g, 74.06 mmol) in anhydrous CH₂Cl₂ (180 mL) and this solution wascooled to −78° C. DMSO (11.57 g, 148.08 -mmol) was added via syringeover a 15 min period during which vigorous gas evolution was observedand the mixture was stirred for 25 min. To the mixture was added1-(3,3-dimethyl-butyl)-pyrrolidin-3-ol (6.34 g, 37.01 mmol) in CH₂Cl₂(20 mL) via syringe over a 10 min period. The mixture was stirred forone h at −78° C., then Et₃N (29.96 g, 296.08 mmol) was added via syringeand the dry ice/acetone bath was removed to allow the reaction mixtureto warm up to room temperature over 2 h.

[0755] The reaction mixture was poured into H₂O (250 mL), the layerswere separated and the aqueous was washed with CH₂Cl₂ (3×150 mL). Theorganic layers were combined and washed with NaHCO₃ (200 mL), brine (200mL), dried over Na₂SO₄, filtered, then concentrated. The product waspurified by column chromatography on SiO₂ using as eluent 100% CH₂Cl₂ toafford the title compound in (3.5 g, 56% yield).

[0756] (c) 3-Amino-1-(3,3-dimethyl-butyl)-pyrrolidine-3-carbonitrile

[0757] To a dry 250 mL round bottom flask set with a condenser was addedsodium cyanide (0.786 g, 16.03 mmol), ammonium chloride (0.904 g, 16.9mmol) and NH₃/MeOH (2.0 M, 15.36 mL, 30.7 mmol). To the mixture wasadded 1-(3,3-dimethyl-butyl)-pyrrolidin-3-one (2.60 g, 15.36 mmol) andMgSO₄ (2.5 g). The mixture was heated at 60° C. in an oil bath andstirred for 4 h. The mixture was cooled to room temperature and filteredto remove the insolubles, the filtrate was concentrated to dryness andthe residue was dissolved in EtOAc/Et₂O and filtered through a pad ofdiatomaceous earth then concentrated to dryness to give the titlecompound in (1.5 g, 51% yield). The crude compound was used in the nextstep without further purification.

[0758] (d)N-(3-Cyano-1-(3,3-dimethyl-butyl)-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0759] DiastereomericN-(3-cyano-1-(3,3-dimethyl-butyl)-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramidewas prepared by a method analogous to that of Example 3-part (d). Thepurification was done by reverse phase preparative HPLC to separate thetwo diastereomers. ¹H NMR (CDCl₃) 6.95 (1H, s), 3.7-3.4 (8H, m),3.1-3.07 (1H, m), 2.9-2.52 (5H, m), 2.45-2.39 (2H, m), 2.3-2.08 (3H, m),1.78-1.6 (5H, m), 1.38-1.3 (2H, m), 1.3-1.1 (5H, m), 0.95-0.78 (12H,m).MS, m/z 461=M+1.

Example 8

[0760]N-(1-cyano-3-piperidin-1-yl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0761] (a) 2-tert-Butoxycarbonylamino-N-methoxy-N-methyl Succinamic AcidBenzyl Ester

[0762] This compound was prepared by a method analogous to that ofExample 3-part (d) from NF, O-Dimethylhydroxylamine hydrochloride and2-tert-Butoxycarbonylamino-succinic acid 1-benzyl ester.

[0763] (b) 2-tert-Butoxycarbonylamino-4-oxo-butyric Acid Benzyl Ester

[0764] To 2-tert-butoxycarbonylamino-N-methoxy-N-methyl succinamic acidbenzyl ester (0.50 g, 1.36 mmol) in THF (5 mL) at −78° C. was addedDIBAL-H (0.233 g, 1.67 mmol) dropwise. The mixture was stirred for 1.5 hand monitored by TLC. When completed the reaction was quenched with 5 mLof saturated solution of Rochell salt (KNaC₄H₄O₆.4H₂O) (potassium sodiumtartrate) and extracted with EtOAc (2×10 mL). The organic layer waswashed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound in quantitative yield (0.40 g).

[0765] (c) 2-tert-Butoxycarbonylamino-4-piperidin-1-yl-butyric AcidBenzyl Ester

[0766] This compound was prepared by a method analogous to that ofExample 5-part (a) from 2-tert-butoxycarbonylamino-4-oxo-butyric acidbenzyl ester and piperidine. The product was dissolved in 20% TFA inCH₂Cl₂ (10 mL) at 0° C., then it was allowed to stir for 1 h at roomtemperature. The solvent was evaporated to give the diamine TFA salt.

[0767] (d)2-(2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-4-piperidin-1-yl-butyricAcid Benzyl Ester

[0768] This compound was prepared by a method analogous to that ofExample 3-part (d) from the above TFA diamine salt and(R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid.

[0769] (e)N-(1-Carbamoyl-3-piperidin-1-yl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0770] To2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-4-piperidin-1-yl-butyricacid benzyl ester (0.10 g, 0.18 mmol) was added NH₃/MeOH (2.0 M, 10 mL)in a sealed tube and the mixture was stirred at room temperature for 3days. The solvent was evaporated to give the title compound in 50%yield.

[0771] (f)N-(1-Cyano-3-piperdin-1-yl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0772] This compound was prepared by a method analogous to that ofExample 1-part (f) fromN-(1-Carbamoyl-3-piperidin-1-yl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.¹H NMR (CDCl₃) 4.98-4.94 (1H, m), 3.74-3.45 (8H, m), 3.05-2.2 (9H, m),2.15-1.4 (11H, m), 1.35-1.05 (7H, m), 0.92-0.75 (3H, m). MS: m/z 433M+1.

Example 9

[0773]N-[3-Cyano-(1H-indol-2-ylmethyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4=yl-4-oxo-butyramide

[0774] (a) 1-(Toluene-4-sulfonyl)-1H-indole-3-carboxaldehyde

[0775] This compound was prepared according to the reference below:

[0776] Chauhan, P. M. S., Chateijee, R. K. Indian J. Chem. Sect. B,1994, 33 (1), 32-37.

[0777] (b)N-{3-Cyano-1-[1-(toluene-4-sulfonyl)-1H-indole-3-ylmethyl]-pyrrolidin-3-yl}-2cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0778] This compound was prepared by a method analogous to that ofExample 3-part (a through d) from1-(toluene-4-sulfonyl)-1H-indole-3-carboxaldehyde and(R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid.

[0779] (c)N-[3-Cyano-1-(1H-indol-2-ylmethyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0780] A suspension ofN-{3-cyano-1-[1-(toluene-4-sulfonyl)-1H-indole-3-ylmethyl]-pyrrolidin-3-yl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide(0.052 g, 0.079 mmol) and Mg (powder) (0.038 g, 1.6 mmol) in MeOH (5 mL)was sonicated at room temperature reaction was monitored by MS. Whencompleted, the reaction mixture was poured into a saturated solution ofNH4Cl and extracted with CH₂Cl₂. The combined organic extracts weredried over Na₂SO₄ and concentrated to provide the title compound in 76%yield. The compound was recrystallized from Et2O/hexanes. 1H NMR (CDCl3)8.1 (1H, s), 7.71-7.69 (1H, m), 7.39-7.37 (1H, m), 7.25-7.15 (3H, m),6.9 (1H, s), 4.0-3.8 (2H, m), 3.7-3.3 (11H, m), 3.2-3.1 (1H, m), 3.0-2.5(3H, m), 2.3-2.15 (2H, m), 1.8-1.4 (5H, m), 1.35-1.03 (5H, m), 0.95-0.78(3H,m). MS, m/z 506=M+1.

[0781] Listed below are additional examples of compounds of theinvention, which were prepared by methods analogous to these describedabove.

[0782] 4-Methyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(2-benzyloxy-1-cyano-ethyl)-amide. MS: m/z=402 M+1

[0783]N-(1-Cyano-3-phenyl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=426 M+1

[0784] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(2-benzyloxy-1-cyano-ethyl)-amide. MS: m/z=416 M+1.

[0785] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(1-cyano-3-phenyl-propyl)-amide. MS: m/z=400 M+1.

[0786]N-(2-Benzyloxy-1-cyano-ethyl)-4-morpholin-4-yl-2-naphthalen-2-ylmethyl-4-oxo-butyramide.MS: m/z=486 M+1.

[0787]N-[2-(4-Chloro-benzyloxy)-1-cyano-ethyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=477 M+1.

[0788]N⁴-[2-(4-Acetylamino-phenyl)-N¹-(2-benzyloxy)-1-cyano-ethyl]-2-cyclohexylmethyl-succinamide.MS: m/z=505 M+1.

[0789] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide. MS: m/z=407 M+1.

[0790] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(1-benzyl-4-cyano-piperidin-4-yl)-amide. MS: m/z=455 M+1.

[0791]N-(1-Benzyl-4-cyano-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=481 M+1.

[0792]N-[1-(3-Benzyloxy-benzyl)-3-cyano-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=573 M+1.

[0793]N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1

[0794]N-[3-Cyano-1-(2,6-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=503 M+1.

[0795]N-[3-Cyano-1-(3,5-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=503 M+1.

[0796]N-[3-Cyano-1-(3-trifluoromethyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=535 M+1.

[0797]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=459 M+1.

[0798]4,4-Dimethyl-2-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=460 M+1.

[0799] 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=447 M+1.

[0800] 4,4-Dimethyl-2-(2-oxo-2-piperidin-1-yl-ethyl)-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=445 M+1.

[0801] 4,4-Dimethyl-2-(2-oxo-2-thiomorpholin-4-yl-ethyl)-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=463 M+1.

[0802]N-(3-Cyano-1-isopropyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=419 M+1.

[0803]N-(3-Cyano-1-methyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=391 M+1.

[0804]N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=447 M+1.

[0805]N-(3-Cyano-1-isobutyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=433 M+1.

[0806]N-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=431 M+1.

[0807]N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=481 M+1.

[0808]N-(3-Cyano-1-methyl-piperidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=405 M+1.

[0809]N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1.

[0810]N-(3-Cyano-1-propyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=419 M+1.

[0811]N-(3-Cyano-1-cyclopentyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=445 M+1.

[0812]N-[1-Cyano-3-(cyclohexyl-ethyl-amino)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=475 M+1.

[0813]N-[3-(Benzyl-isopropyl-amino)-1-cyano-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=497 M+1.

[0814]N-(3-Cyano-1-cycloheptyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=473 M+1.

[0815]N-[3-Cyano-1-(1,2,3,4-tetrahydro-naphthalen-1-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=507 M+1.

[0816]N-(1-Bicyclo[2.2.1]hept-2-yl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=471 M+1.

[0817]N-(4-Cyano-1-propyl-piperidin-4-yl)-2-cyclohexyhethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=433 M+1.

[0818]N-(1-Benzyl-4-cyano-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.MS: m/z=487 M+1.

[0819]N-[3-Cyano-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 461=M+1. (1:1 mixture of diastereomers)

[0820]N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexyhnethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 477=M+1. (single diastereomer)

[0821]N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z 477=M+1 (single diastereomer)

[0822]N-[3-Cyano-1-(2-phenyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 543=M+1

[0823]N-[3-Cyano-1-(3-phenyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 543=M+1

[0824]N-4-Cyano-2-phenethyl-2H-pyrazol-3-yl)-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0825] N-(4-Cyano-1-phenethyl-1H-pyrazol-3-yl)-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0826]N-[(3S)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0827]N-[(3R)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0828]N-[(S)-Cyano-methyl-phenyl-methyl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0829]N-[(R)-Cyano-methyl-phenyl-methyl]-(2R)-2-cyclohexyhnethyl-4-morpholin-4-yl-4-oxo-butyramide

[0830]N-[(S)-Cyano-methyl-pyridin-4-yl-methyl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0831]N-[(R)-Cyano-methyl-pyridin-4-yl-methyl]-(2R)-2-cyclohexyhnethyl-4-morpholin-4-yl-4-oxo-butyramide

[0832]N-[(3S)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0833]N-[(3R)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0834]N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0835]N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0836]N-[(3S)-3-Cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexyhethyl-4-morpholin-4-yl-4-oxo-butyramide

[0837]N-[(3R)-3-Cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0838]N⁴-Carbamoylmethyl-N¹-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-N⁴-methyl-succinamide:C₂₅H₄₁N₅O₃, ESMS: 460 (M+1)

[0839] {1-[3-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-4-cyclohexyl-butyryl]-pyrrolidin-3-yl}-carbamic acidtert-butyl ester. MS: m/z=566.5 M+1

[0840] {1-[3-(3-Cyano-1-cyclohexyl -pyrrolidin-3-ylcarbamoyl)-4-cyclohexyl-butyryl]-pyrrolidin-3-yl}-carbamic acidtert-butyl ester. MS: m/z=558.6 M+1

[0841]N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-dimethylamino-pyrrolidin-1-yl)-4-oxo-butyramide.MS: m/z=494.5 M+1

[0842]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-4-oxo-butyramide.MS: m/z=471 M+1

[0843]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(2,6-dimethyl-morpholin-4-yl)-4-oxo-butyramide.MS: m/z=487 M+1

[0844]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(2-methoxymethyl-morpholin-4-yl)4-oxo-butyramide.MS: m/z=503 M+1.

Example 10

[0845]N-{1-[(Benzyl-methyl-amino)-methyl]-1-cyano-3-phenyl-propyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0846] (a) (Benzyl-methyl-amino)-acetic acid Methyl Ester

[0847] Methyl bromoacetate (10 g, 65.4 mmol, 1.0 equiv) was dissolved in100 mL of CH₂Cl₂ which was then cooled to 0° C. N-Methylbenzylamine(7.92 g, 65.4 mmol, 1.0 equiv) was added dropwise over a 10 min periodat which time Hunig's base (21 g, 163 mmol, 2.4 equiv) was added and thereaction was allowed to warm to room temperature and was stirred for 16h. The reaction was diluted with 50 mL of saturated bicarbarbonate andthe layers were separated. The organic layer was washed once more with50 mL of sodium bicarbonate, dried over Na₂SO₄, decanted andconcentrated to a yellow oil which was used in the next step withoutfurther purification.

[0848] (b)(Benzyl-methyl-amino)-acetic Acid Hydrochloride Salt.

[0849] (Benzyl-methyl-amino)-acetic acid methyl ester (12 g, 62.1 mmol,1.0 equiv) was dissolved in 50 mL of MeOH to which was added a solutionof LiOH hydrate (8.23 g, 196 mmol, 3.0 equiv) in 50 mL of water. Themixture was stirred at room temperature for 1.3 h at which time TLC (5%MeOH in CH₂Cl₂) indicated consumption of the starting material. Thereaction solution was washed 1×50 mL of Et₂O and then the aqueous layerwas acidified to pH 1 with concentrated HCl. The mixture was thenevaporated to dryness under high vacuum. The resulting solid wastriturated with EtOH (200 mL) and the mixture was filtered. The filtratewas then concentrated to dryness to yield a white cystalline solid thatwas used without further purification.

[0850] (c) 2-(Benzyl-methyl-amino)-N-methoxy-N-methy-acetamide.

[0851] (Benzyl-methyl-amino)-acetic acid hydrochloride salt (12 g, 56mmol, 1.0 equiv) was mixed in DMF (200 mL) along with EDC (1 0.6 g, 56mmol, 1.0 equiv) for 15 min. N, o-Dimethylhydroxylamine hydrochloride(6.52 g, 67 mmol, 1.2 equiv) was added to the reaction followed byN-methylmorpholine (34 mL, 334 mmol, 6.0 equiv). The reaction wasstirred for 16 h. The DMF was removed in vacuo and the residue wasredissolved in 200 mL of EtOAc. The solution was washed once with 200 mLbrine. The organic layer was dried over Na₂SO₄, decanted andconcentrated to yield the desired product as a free-flowing oil (12.6 g,80%) that was used in the next step without further purification; MS,m/z 223=M+1.

[0852] (d) 1-(Benzyl-methyl-amino)-4-phenyl-butan-2-one.

[0853] 2-(Benzyl-methyl-amino)-N-methoxy-N-methyl-acetamide (2.0 g, 9.0mmol, 1.0 equiv) was dissolved in 30 mL of dry THF under argon. Thesolution was cooled to −78° C. and a 1 M solution of phenethyl magnesiumchloride (12.6 mL, 12.6 mmol, 1.4 equiv) was added dropwise of a periodof 1 min. The resulting mixture was stirred at −78° C. for 3 h, warmedto 0° C. for 20 min and recooled to −78° C. at which time the reactionwas quenched by the addition of 5 mL of saturated sodium bicarbonate.The reaction solution was diluted with 200 mL of EtOAc and 200 mL ofwater. The layers were separated and the organic layer was dried overNa₂SO₄, decanted and concentrated to an oil (2.4 g, 100%) which was usedwithout further purification; MS, m/z 268=M+1.

[0854] (e)2-Amino-2-[(benzyl-methyl-amino)-methyl]-4-phenyl-butyronitrile.

[0855] 1-(Benzyl-methyl-amino)-4-phenyl-butan-2-one (2.4 g, 9.0 mmol,1.0 equiv) was mixed in 36 mL of 2.0 M NH₃ in MeOH. To the solution wasadded NaCN (0.484 g, 9.9 mmol, 1.1 equiv) and NH₄Cl (0.528 g, 9.9 mmol,1.1 equiv). The resulting mixture was refluxed for 2 h at which time anaddition 15 mL of 2.0 M NH₃ in MeOH was added and the mixture wasrefluxed another 4 h. Though TLC (5% MeOH in CH₂Cl₂) still showed thepresence of the ketone, the reaction was cooled and filtered. Thefiltrate was concentrated and the crude product was purified by flashchromatography on SiO₂ using 60% hexanes in CH₂Cl₂ then 1.5% MeOH to 3%MeOH was added. The desired product was isolated pure (0.561 g, 21%) asa yellow oil that crystallized upon standing at −20° C.; MS, m/z294=M+1.

[0856] (f)N-{1-[(benzyl-methyl-amino)-methyl]-1-cyano-3-phenyl-propyl}-2-cyclohexylmethyl-4-morpholin-4-yl-oxo-butyramide.

[0857] 2-Cyclohexylmethyl-4-morpholin-4-yl-oxo-butanoic acid (0.097 g,0.34 mmol, 1.0 equiv) was dissolved in 10 mL of CH₂Cl₂ followed byaddition of EDC (0.065 g, 0.34 mmol, 1.0 equiv). The solution wasstirred for 15 min at which time a solution of2-amino-2-[(benzyl-methyl-amino)-methyl]-4-phenyl-butyronitrile (0.10 g,0.34 mmol, 1.0 equiv) in 5 mL of CH₂Cl₂ was added followed byN-methylmorpholine (0.137 g, 1.36 mmol, 4.0 equiv). The resultingsolution was stirred at room temperature for 72 h. The volatiles wereremoved in vacuo and the residue was redissolved in 100 mL of EtOAc andthe solution was washed 2×25 mL brine. The organic layer was evaporatedto dryness and the crude product was purified by semi-prep reverse-phaseHPLC using 40% CH₃CN in water to 90% over a time of 25 min. Theappropriate fractions were combined and concentrated to yield thedesired product as a thick oil (0.047 g, 25%); MS, m/z 559 M+1.

Example 11

[0858]N-(4-Cyano-1,2-dimethyl-piperidin-4-yl-2-cycloheyxlmethyl-4-morpholin-4-yl-4-oxo-butyramide.

[0859] (a) 3-(Benzyl-methyl-amino)-butyric Acid Methyl Ester.

[0860] Benzyl-methyl-amine (20 g, 165 mmol, 1.0 equiv) was added neat tomethyl crotonate (19.8 g, 198 mmol, 1.2 equiv). The resulting solutionwas stirred at room temperature for 72 h. The excess crotonic ester wasremoved in vacuo to yield the desired product (40.3 g, -100%) which wasused without further purification; MS, m/z 222=M+1.

[0861] (b) 3-Methylamino-butyric Acid Methyl Ester.

[0862] 3-(Benzyl-methyl-amino)-butyric acid methyl ester (15 g, 67.8mmol, 1.0 equiv) was placed in a Parr hydrogenation bottle and dissolvedin 50 mL of MeOH. 20% Palladium hydroxide on carbon (0.5 g, 0.94 mmol,0.014 equiv) was added and the mixture was shaken at 50 psi H₂ for 16 h.The reaction was judged as complete when the uptake of H₂ had stopped.The bottle was opened and 10 g of diatomaceous earth in 100 mL of MeOHwas added. The mixture was filtered on a pad of diatomaceous earth whichwas then washed with 2×100 mL of MeOH. The filtrates were combined andconcentrated in vacuo to yield the desired product as an oil that issomewhat volatile (7.6 g, 85%). The crude product was used withoutfurther purification; MS, m/z 132=M+1.

[0863] (c) 3-[(2-Methoxycarbonyl-ethyl)-methyl-amino]-butyric AcidMethyl Ester.

[0864] 3-Methylamino-butyric acid methyl ester (7.6 g, 58 mmol, 1.0equiv) was added neat t0 methyl acrylate (7.5 g, 87 mmol, 1.5 equiv).The resulting solution was refluxed for 16 h. The reaction was cooledand diluted with hexanes (200 mL) and an insoluble polymer separatedout. The hexane solution was decanted and the polymer was washed 2×100mL hexanes with vigorous stirring. The combined hexane solutions werethen concentrated in vacuo. The crude product was purified by flashchromatography on SiO₂ using pure CH₂Cl₂ as an eluent. The pure productwas isolated as a clear colorless oil (7.3 g, 58%); MS, m/z 218=M+1.

[0865] (d) 1,2-Di-methyl-4-piperidone.

[0866] A 1 M solution of TiCl₄ in CH₂Cl₂ (23 mL, 23 mmol, 1.0 equiv) wasadded to a flask under Ar and cooled to −15° C. with a MeOH/ice waterbath. 3-[(2-Methoxycarbonyl-ethyl)-methyl-amino]-butyric acid methylester (5 g, 23 mmol, 1.0 equiv) was added dropwise over a 25 min periodas solution in 75 ml of dry CH₂Cl₂ to give a dark red mixture that wasdifficult to stir with a magnetic stir bar. Stirring was continued anadditional 1 h and then Et₃N (5.1 g, 50.6 mmol, 2.2 equiv) was addeddropwise over a 30 min period and then the reaction was stirred anadditional 1.5 h at −15° C. The reaction mixture was poured into 150 mLof brine and 150 mL of CH₂Cl₂ was added. After thorough mixing, the pHof the water was brought to 8-9 With Et₃N. The mixture was filtered andthe gel-like solid was washed 3×100 mL CH₂Cl₂. The filtrate layers wereseparated and the aqueous layer was washed with 3×50 mL CH₂Cl₂. All ofthe organic layers were combined and concentrated to a thick red oil.The residue was taken up in 150 mL of concentrated HCl and the solutionwas refluxed 4 h. The cooled reaction solution was evaporated to drynessand the residue was dissolved in 200 mL of saturated sodium bicarbonate.The product ketone was extracted with 2×100 mL of EtOAc. The organiclayers were combined and dried over Na₂SO₄. The product was purified byflash chromatography on SiO₂ using CH₂Cl₂ to 4% MeOH in CH₂Cl₂ aseluent. The product was isolated as an orange oil (1.23 g, 42%); MS, m/z128=M+1.

[0867] (e) 4-Amino-4-cyano-1,2-dimethyl-piperidine.

[0868] 1,2-Dimethyl-4-piperidone (1.23 g, 9.67 mmol, 1.0 equiv) wasdissolved in 39 mL of 2 M NH₃ in MeOH (8 equiv NH₃). To this solutionwas added NaCN (0.52 g, 10.6 mmol, 1.1 equiv) and NH₄Cl (0.57 g, 10.6mmol, 1.1 equiv). The resulting mixture was refluxed for 2 h at whichtime an additional 39 mL of 2 M NH₃ in MeOH was added followed by anadditional 2 h of reflux. The reaction was cooled and filtered. Thefiltrate was concentrated and taken up in 100 mL of CH₂Cl₂ giving moresalt precipitate which was removed by a second filtration. The filtratewas then concentrated to a thick orange oil (1.32 g, 89%). ¹H NMR showeda 3 to 1 mixture of diastereomers of unknown configuration. The crudeproduct was used without further purification; MS, m/z 154=M+1.

[0869] (f)N-(4-Cyano-1,2-dimethyl-piperidin-4-yl)-2-cycloheyxlmethyl-4-morpholin-4-yl-4-oxo-butyramide.

[0870] 2-Cyclohexylmethyl-4-morpholin-4-yl-oxo-butanoic acid (0.3 g,1.06 mmol, 1.0 equiv) was mixed with EDC (0.2 g, 1.06 mmol, 1.0 equiv)in 15 mL of DMF. A solution of 4-amino-4-cyano-1,2-dimethyl-piperidine(0.16 g, 1.0 mmol, 0.95 equiv) in 5 mL of DMF was added followed byaddition of N-methylmorpholine (0.43 g, 4.24 mmol, 4.0 equiv). Theresulting solution was stirred for 16 h. The reaction was diluted with50 mL of saturated sodium bicarbonate and the product was extracted with3×50 mL EtOAc. The organic layers were combined and concentrated invacuo. The crude product was purified by semi-prep reverse-phase HPLCusing 20% CH₃CN in water to 61% CH₃CN in water over a gradient time of17 min. The product was isolated in two peaks as an undefined mixture ofdiastereomers about the piperidine ring; MS, m/z 419=M+1 for both HPLCpeaks.

Example 12

[0871](4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide

[0872] (a) 3-(4-Methyl-cyclohexyl)-acrylic Acid Ethyl Ester

[0873] Lithium aluminium hydride (560 mg, 60 mmol) was suspended in 20mL of dry THF. To this suspension at −78° C. under nitrogen was added asolution of trans-4-methyl-1-cyclohexanecarboxylic acid (2.13 g, 15mmol) in 20 mL of dry THF. This reaction mixture was stirred at −78° C.for 2 h and then warmed up to room temperature in 2 h. The reaction wascooled to 0° C., and quenched with a saturated solution of potassiumsodium tartrate and extracted repeatedly with diethyl ether. Thecombined organic phases were dried over magnesium sulfate and evaporatedunder reduced pressure to give a clear oil. Yield 100%.

[0874] To a solution of oxalyl chloride (1.76 mL, 20 mmol) in 60 mL ofdry dichloromethane at −78° C. under nitrogen was added DMSO (2.84 mL,40 mmol). After the gas evolution stopped, the above oil (1.28 g, 10mmol) dissolved in 10 mL of dichloromethane was added. The reactionmixture was stirred at −78° C. for 1 h and triethylamine (7 mL, 50 mmol)was added. The reaction was then allowed to warm up to room temperaturein 2 h and was quenched with water. The aqueous phase was extractedrepeatedly with dichloromethane. The combined organic phases were washedwith brine and dried over magnesium sulfate. The solvent was removedunder reduced pressure to give a yellow oil, which was used in the nextstep without further purification. Yield: 1.06 g, 84%.

[0875] The above oil (1.06 g, 8.41 mmol) and(carbethoxymethylene)triphenylphosphorane (2.93 g, 8.41 mmol) wereheated under reflux in 30 mL of dry toluene under nitrogen for 2 h. Thesolvent was removed under reduced pressure and the residue was purifiedby silica gel flash chromatography eluting with 5% diethyl ether inpetroleum ether to give a clear oil. Yield: 1.45 g, 88%.

[0876] (b) 3-(4-Methyl-cyclohexyl)-propionic Acid.

[0877] The above oil (1.45 g, 7.39 mmol) was dissolved in 20 mL of EtOHand hydrogenated in a Parr apparatus under 50 psi of H₂ in the presenceof 10% palladium on activated charcoal for 2 h. The solid was removed byfiltration and washed with EtOH. The filtrate was evaporated underreduced pressure to give the ethyl ester as a clear oil. Yield: 1.37 g,94%.

[0878] The above ester (1.37 g, 6.98 mmol) was dissolved in 20 mL ofTHF. A 2 M lithium hydroxide solution (50 mL) was added. This reactionmixture was stirred at room temperature for 16 h. The solution wascooled to 0° C., and acidified with 6 N HCl to pH 2. The resulting whiteprecipitate was collected by filtration and washed with water then driedunder vacuum giving the desired acid. Yield: 1.08 g, 91%.

[0879] (c)(S)-4-Isopropyl-3-[3-(4-methyl-cyclohexyl)-propionyl]-oxazolidin-2-one.

[0880] The acid (1.02, 6 mmol) was dissolved in 20 mL of drydichloromethane and 1 drop of DMF. To this solution at 0° C. was addedoxalyl chloride (1.57 mL, 18 mmol). The reaction mixture was stirred atroom temperature for 2 h. The solvent was removed under reduced pressureand the resulting acid chloride was used in the next reaction withoutfurther purification.

[0881] (S)-(−)-4-Isopropyl-2-oxazolidinone (0.775 g, 6 mmol) wasdissolved in 20 mL of dry THF. To this solution at −78° C., undernitrogen was added n-butyl lithium (2.5 M, 2.4 mL, 6 mmol). The reactionmixture was stirred at −78° C. for 30 min and then at room temperaturefor 30 min. To this solution at −78° C. was added the acid chloridedissolved in 20 mL of THF. The reaction was maintained at −78° C. for 1h then warmed up to room temperature in 2 h and quenched with 1Mpotassium carbonate solution. The aqueous phase was extracted repeatedlywith diethyl ether. The combined organic phases were washed with brineand dried over magnesium sulfate. The solvent was removed under reducedpressure. The residue was purified by silica gel flash chromatography,eluted with 5% diethyl ether in petroleum ether to give a clear oil.Yield: 1.39 g, 82%.

[0882] (d)(2R,4′S)-1-(4-Isopropyl-2-oxo-oxazoldin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-butane-1,4-dione.

[0883] The above compound (0.703 g, 2.5 mmol) was dissolved in 20 mL ofdry THF. To this solution at −78° C. and under nitrogen was added sodiumbis(trimethylsilyl)amide (0.6 M, 4.2 mL, 2,5 mmol). The reaction mixturewas stirred at −78° C. for 1 h. 2-Bromo-1-morpholin-4-yl-ethanone (W. J.Thompson, et al., J.Med.Chem, 1992 35 1685-1701) (0.52 g, 2.5 mmol)dissolved in 10 mL of dry THF was added to the above reaction mixture.This solution was maintained at −78° C. for 1 h, warmed up to roomtemperature in 2 h and -quenched with saturated ammonium chloridesolution. The aqueous phase was extracted repeatedly withdichloromethane. The combined organic phases were washed with brine anddried over magnesium sulfate. The solvent was removed under reducedpressure. The residue was purified by silica gel flash chromatography,eluting with 1% MeOH in dichloromethane to give a white solid. Yield:0.82 g, 80%.

[0884] (e)(R)-2-(4-Methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyric Acid.

[0885] The above solid (0.82 g, 1.96 mmol) was dissolved in 30 mL of THFand 10 mL of water. To this solution, at 0° C. was added 30 mL of 30%hydrogen peroxide. The reaction mixture was stirred at 0° C. for 2 h andthen quenched with sodium sulfite. This solution was acidified with 6 NHCl to pH 2 and then extracted repeatedly with dichloromethane. Thecombined organic phases were washed with brine and dried over magnesiumsulfate. The solvent was removed under reduced pressure. The residue waspurified by silica gel flash chromatography, eluted with 2% MeOH indichloromethane to give a white solid. Yield: 0.31 g, 53%.

[0886] (f)(4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide.

[0887] The title compound was prepared using the above intermediatefollowing the procedure described in Example 6, C₂₇H₄₄N₄O₃, ESMS: 473(M+1)

[0888] Additional compounds of the present invention prepared by methodsanalogous to those above include:

[0889](4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(1-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide:C₂₇H₄₄N₄O₃, ESMS: 473 (M+1

Example 13

[0890]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(trans-4-phenyl-cyclohexylmethyl)-butyramide.

[0891] (a) 4-Phenyl-cyclohexanecarboxylic Acid.

[0892] To a mixture of AlCl₃ (13 g, 97.5 mmol, 1.0 equiv) in benzene(100 mL) kept at 35° C., was added 1-cyclohexenecarboxylic acid (5 g,39.7 mmol, 0.41 equiv) dropwise. After addition was complete, thereaction solution was heated to 70° C. for 1 h and 45° C. overnight. Thereaction was cooled, and 200 mL of 1 N HCl was slowly added. The productwas extracted with EtOAc. The organic layer was extracted with 1 N NaOHand the aqueous layer was acidified with concentrated HCl to produce awhite precipitate that was collected by filtration, washed with waterand dried to give the titled compound as a white solid (3.1 g, 38%)which was used without further purification.

[0893] (b) 4-Phenyl-cyclohexylmethanol.

[0894] A suspension of LiAlH₄ (0.56 g, 14.8 mmol, 2.0 equiv) wasprepared under argon in 50 mL of anhydrous THF (50 mL) kept at 0° C. Asolution of 4-phenyl-cyclohexanecarboxylic acid (1.5 g, 7.34 mmol, 1.0equiv) in 50 mL of THF was added dropwise over a 20 min period. Thereaction mixture was stirred at ambient temperature for 1.5 h and thencooled to 0° C. The excess hydride reagent was carefully quenched underargon by dropwise addition of 1 N HCl. After quenching, the reactionmixture was extracted with EtOAc. The organic layer was dried overMgSO₄, filtered and concentrated to give the title product as acolorless oil (1.9 g crude) which was used without further purification.

[0895] (c) 4-Phenyl-cyclohexylmethyl-p-toluene sulfonate.

[0896] 4-Phenyl-cyclohexylmethanol (2.5 g, 13.1 mmol, 1.0 equiv) wasdissolved in chloroform (50 mL) and pyridine (2.1 g, 26.3 mmol, 2.0equiv) was added and the mixture was cooled to 0° C. A solution of tosylchloride (3.75 g, 19.7 mmol, 1.5 equiv) in chloroform (30 mL) was addedand the resulting solution was stirred at ambient temperature for 30min. The reaction was diluted with EtOAc (150 mL) and washed 2×100 mL 1NHCl. The organic layer was then washed with 1×100 mL saturated sodiumbicarbonate, dried over MgSO₄, filtered and concentrated to yield asolid which was used immediately in the next step without furtherpurification.

[0897] (d) (4-Phenyl-cyclohexylmethyl)-malonic Acid Diethyl Ester.

[0898] Diethyl malonate (3.1 g, 19.7 mmol, 1.5 equiv) was added dropwiseto a solution of sodium (1.25 g, 54.0 mmol, 4.0 equiv) in EtOH (50 mL).4-Phenyl-cyclohexylmethyl-p-toluene sulfonate (˜13.1 mmol, ˜1.0 equiv,the crude product from the previous step) was added as a solution in 50mL of EtOH. The resulting mixture was refluxed for 8 h. The reactionmixture was cooled and evaporated to dryness and then dissolved in water(150 mL) and the crude product extracted with 3×100 mL EtOAc. Theorganic layer was dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by flash chromatography on SiO2 using 10% EtOAc inhexanes to give the desired product as a colorless oil (2.79 g).

[0899] (e) 3-(4-Phenyl-cyclohexylmethyl)-propanoic Acid.

[0900] (4-Phenyl-cyclohexylmethyl)-malonic acid diethyl ester (2.79 g,8.4 mmol, 1.0 equiv) was added to a solution of potassium hydroxide(2.35 g, 41 mmol, 5 equiv) in 20 mL of water and 20 mL of MeOH. Theresulting mixture was refluxed for 0.5 h and then evaporated to drynessand then dissolved in 100 mL of water. The solution was washed 3×100 mLwith hexane and then brought to pH <1 with concentrated HCl. The productwas extracted 3×100 mL EtOAc. The organic layers were combined andconcentrated to dryness. The crude product was then heated for 10 min at180° C. to decarboxylate the diacid and yield the monoacid (0.9 g) whichwas used without further purification.

[0901] (f)N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(trans-4-phenyl-cyclohexylmethyl)-butyramide;

[0902] The title compound was prepared using the intermediate from stepe above and the procedures reported in Example 12, MS, m/z 535=M+1

Example 14

[0903]2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(3-eyano-1cyohexyl-pyrroldin-3-yl)-4-morpholin-4-yl-4-oxo-butyramide.

[0904] (a) 2-Bicyclo[4.1.0]hept-7-yl-carboxylic Acid Ethyl Ester.

[0905] A mixture of cupric triflate (0.1 g, 0.28 mmol, 0.0016 equiv) wasprepared in cyclohexene (100 mL). A 25 mL of a solution of ethyldiazoacetate (20 g, 175 mmol, 1.0 equiv) in cyclohexene (100 mL) wasadded to initiate the reaction followed by dropwise addition of theremainder to maintain a gentle exothermic reaction. The reaction wasthen stirred 18 h at room temperature. 200 mg of additional cuprictriflate was added to decompose any unreacted diazo acetate and then themixture was concentrated to dryness. The residue was distilled on awater bath to yield the desired product as a colorless oil (15.7 g).

[0906] (b)2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-butyramide.

[0907]2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-butyramidewas prepared using the procedures outlined in Example 13 and theintermediate generated in step a above; MS, m/z 471=M+1.

[0908] Additional compounds of the present invention prepared by methodsanalogous to those above include:

[0909]2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(4-cyano-1-methyl-piperidin-4-yl)-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 417=M+1.

[0910]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-butyramide;MS, m/z 507=M+1

[0911]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-indan-2-ylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 493=M+1.

[0912]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclopentylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS, m/z 445=M+1.

Example 15

[0913][2-Cyano-2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-ethyl]-carbamicacid tert-butyl Ester.

[0914] (a)3-tert-Butoxycarbonylamino-2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-propionicacid methyl ester was prepared by the procedure described in Example 1from (R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (0.25 g,0.88 mmol), EDC (0.22 g, 1.15 mmol), I-hydroxybenzotriazole (0.155 g,0.1.15 mmol) and the HCl salt of N-Beta-Boc-Alpha-Beta-Diaminopropionicacid methyl ester (0.25 g, 0.98 mmol) to yield a white solid (0.36 g,84.5%) after purification by flash column chromatography. MS: m/z484=M+1

[0915] (b) The above product (0.36 g, 0.745 mmol) was dissolved in 25 mLof 2M ammonia in MeOH. The reaction was cooled to 5° C. and saturatedwith ammonia. The reaction was stoppered and left at room temperatureovernight. The volatiles were removed to give the corresponding amide[2-Carbamoyl-2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-ethyl]-carbamicacid tert-butyl ester (0.34 g, 97.5%). MS: m/z 469=M+1

[0916] (c) The amide from the step above (0.050 g, 0.107 mmol) andcyanuric chloride (0.020, 0.108 mmol) were reacted as described by theprocedure in Example 1. The residue was purified by chromatography(SiO₂, 5% MeOH in CH₂Cl₂) to give the title compound as a white solid(0.02, 48%); ¹H NMR (CDCl₃) 6.83-6.81(1H, d), 5.49(1H, m), 4.93(1H, s),3.68-3.44(8H, m), 2.79-2.73(2H, m), 2.32(1H, d), 1.7-1.59(8H, m),1.44(9H,s), 1.25-1.11(4H, m), 0.89-0.86(3H, m). MS: m/z 451=M+1

Example 16

[0917]N-{Cyano-[(cyclohexyl-ethyl-amino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.

[0918] (a) To[2-Carbamoyl-2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-ethyl]-carbamicacid tert-butyl ester (0.5 g, 0.32 mmol) in 5 mL methylene chloride atroom temperature was added 0.5 mL of TFA. The reaction was stirred for 1h and the volatiles removed. The residue was used for the next stepwithout further purification. MS: nl/z=369 M+1.

[0919] (b) To the aboveN-(2-Amino-1-carbamoyl-ethyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramideTFA salt (0.154 g, 0.32 mmol) in 10 mL THF was added cyclohexanone (0.62g, 0.64 mmol). The reaction was cooled to 0° C. and sodiumtriacetoxyborohydride was added (0.176 g, 0.83 mmol) and the reactionwas allowed to warm up to room temperature overnight. The reactionmixture was cooled in an ice bath and acetaldehyde (0.1 mL, excess) wasadded. The ice bath was removed and the reaction was stirred for 2h. Thereaction was quenched with saturated sodium bicarbonate solution,extracted with EtOAc and dried over anhydrous sodium sulfate. Thevolatiles were removed and the crude product was purified by flashcolumn chromatography (SiO₂, 5% MeOH in CH₂Cl₂) to give the desiredproduct (0.1 g, 65.5%). MS: m/z=479 M+1.

[0920] (c) The amide from the step above (0.070 g, 0.146 mmol) andcyanuric chloride (0.054 g, 0.292 mmol) were reacted as described by theprocedure in Example 1. The residue was purified by chromatography(SiO₂, 5% MeOH in CH₂Cl₂) to give the title compound as a white solid(0.035 g, 51.9%); ¹H NMR (CDCl₃), 4.64-4.59(1H, m), 3.66-3.62 (6H, m),3.56 (2H, m), 3.45 (2H, m), 2.86-2.7 (5H, m), 2.62 (2H, m), 2.5 (1H, m),2.3 (1H, m), 1.78 (6H, m), 1.6 (5H, m), 1.26 (6H, m), 1.1 (3H, t), 0.85(3H, m). MS: m/z=461 M+1

[0921] The following compound was synthesized using the above procedure:

[0922]N-{Cyano-[(dibenzylamino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z=531 M+1

Example 17

[0923]N-{[(Benzyl-ethyl-amino)-methyl]-cyano-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.

[0924] (a) To 1N HCl/MeOH (50 mL) at 0° C. was added(S)-2-Amino-3-benzylamino-propanoic acid(0.5 g, 2.57 mmol). Reaction wasstirred at room temperature overnight. Volatiles were removed to givethe product 2-Amino-3-benzylamino-propanoic acid methyl esterdihydrochloride salt as a white solid (0.7 g, 97.5%). MS: m/z=209 M+1

[0925] (b) The title compound was synthesized according to the schemeusing the procedures in Example 2. The diastereomers were separated viaflash column chromatography to giveN--{[(Benzyl-ethyl-amino)-methyl]-cyano-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,MS: m/z=469 M+1

Example 18

[0926]N-(Cyano-piperidin-1-ylmethyl-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.

[0927] (a) To sodium carbonate (1.13 g, 10.67 mmol) in water (10 mL) andTHF (15 mL) at 0° C. was added L-serine amide hydrochloride (1.0 g, 7.1mmol). The reaction was stirred for 5 min and then benzyl chloroformatewas added (1.2 g, 7.1 mmol). The reaction was allowed to warm up to roomtemperature and stirred for 4 h. Volatiles were removed and the residuewas extracted with methylene chloride/EtOAc (2:1). The organic fractionwas dried over anhydrous sodium sulfate and evaporated to give the CBzprotected serine amide as a white solid (1.0 g, 59%). NMR and MS wereconsistent with the desired product.

[0928] (b) To the above CBz protected serine amide (0.5 g, 2.1 mmol) indry pyridine(3 mL) at 0° C. was added methanesulfonyl chloride (0.2 mL,2.52 mmol) dropwise. After addition was complete, the reaction wasstirred for 2 h at 0° C. It was poured over 10 mL of cold aqueous 1N HCland extracted with EtOAc (2×25 mL). The combined organic fractions werewashed with saturated sodium bicarbonate, brine and dried over anhydroussodium sulfate. Removal of volatiles afforded the desired product as awhite solid (0.6 g, 90.5%). NMR and MS were consistent with the desiredproduct.

[0929] (c) The above mesylate (0.4 g, 1.26 mmol) was dissolved in MeOH(8 mL) at 0° C. and to this was added sodium carbonate (0.13 g, 1.26mmol) and piperidine (0.11 g, 1.26 mmol). The reaction was stirred at 0°C. for 6 h. Solvent was removed and the residue was extracted withEtOAc. The solid was filtered off, filtrate evaporated and purified byflash column chromatography (Silica gel, 5%CH₃OH/CH₂Cl₂). The desiredpiperidine serine amide was obtained as a white solid (0.3 g, 77%). NMRand MS consistent with desired product. MS: m/z=306 M+1.

[0930] (d) The above piperidine compound (0.09 g, 0.29 mmol) wasdissolved in MeOH (15 mL) and subjected to transfer hydrogenation usingcyclohexene (3 mL) and palladium hydroxide on carbon (0.020 g ). Thereaction was heated at 70° C. for 45 min., cooled and filtered overdiatomaceous earth. Removal of solvent gave the free amine (0.04 g,79.3% ). NMR and MS consistent with desired product. MS: r/z=172 M+1.

[0931] (e) The above amine was further coupled and then dehydrated usingconditions described in Example 2, giving the target compound:N-(Cyano-piperidin-1-ylmethyl-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide,¹H NMR (CDCl₃)m), 4.75 (1H, m), 3.67 (5H, m), 3.55 (2H, m), 3.44 (1H,m), 2.7 (3H, m), 2.57 (2H,m), 2.45 (2H, m), 2.31 (1H, m), 1.7 (6H, m),1.4 (3H, m), 1.2 (8H, m), 0.89 (3H, m). MS: m/z=419 M+1.

Example 19

[0932]N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)-4-oxo-butyramide.

[0933]N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)-4-oxo-butyramidewas prepared via a slight modification of Example 6. A3-tert-butoxycarbonyl amino pyrrolidine was coupled to (R )-2-cyclohexylmethyl succinic acid 1-methyl ester. The Boc protecting group wasremoved with HCl/dioxane and the resulting amino pyrrolidine wasalkylated with methanesulfonyl chloride. This intermediate was thencarried through the standard synthetic sequence outlined in Example 6 togive the title compound; MS: m/z=544.4 M+1.

[0934] The following compound was synthesized using the above procedure:

[0935]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)-4-oxo-butyramide.MS: m/z 536.4 M+1.

Example 20

[0936]N-[(3R)-3-Cyano-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.

[0937] (a) N-Benzyloxycarbonyl-(R)-3-hydroxypyrrolidine.

[0938] To a stirred mixture of (R)-3-hydroxypyrrolidine (4.35 g, 50mmol) in THF (50 mL) and aqueous sodium carbonate (10.6 g, 100 mmol in50 mL water) cooled to 0° C. was added a solution of benzylchloroformate in THF (60 mmol, 8.6 mL in 10 mL THF) over a period of5-10 min. After stirring at 0° C. for 2 h, the reaction mixture wasdiluted with 200 mL water and extracted with methylene chloride (3×100mL). The combined extracts were washed with 1N sulfuric acid (3×75 mL)followed by brine solution (3×50 mL). This extract was then dried overanhydrous sodium sulfate and the solvent evaporated to give a lightyellow oil (10.5 g, 95% yield) which was used for the next reactionwithout any purification.

[0939] (b)(3R)-3-Cyano-3-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-pyrrolidine-1-carboxylicAcid Benzyl Ester.

[0940] The title compound was prepared using the procedures outlined inExample 6 and the intermediate generated from step a. above.

[0941] (c) Hydrogenolysis of(3R)-3-cyano-3-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-pyrrolidine-1-carboxylicAcid Benzyl Ester.

[0942] A solution of the CBZ-compd., (1.8 g, 3.53 mmol) in EtOH (75 ML)was stirred under an atmosphere of hydrogen gas along with 10%palladium-carbon (0.3 g). After 1 h catalyst was filtered through adiatomaceous earth and the solvent evaporated to give a thick colorlessoil (1.26 g, 95%) and was used without purification.

[0943] (d) Reductive Amination

[0944] To a stirred solution of the amine (0.3 mmol, 113 mg) and the3,3-dimethylcyclohexanone (1 mmol, 126 mg) in 1,2-dichloroethane (1 mL)was added sodium triacetoxyborohydride (0.3 mmol, 66 mg). After 2 h thereaction mixture was diluted with 10 mL methylene chloride, washed withwater (3×5 mL) and the solvent was evaporated from the organic layer togive a colorless oil which was taken up in 50% aqueous acetonitrile andpurified by reverse phase hplc. The later eluting peak was characterizedto beN-[(3R)-3-cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;(MH+487, ¹H NMR (DMSO-d6) 0.5-1.7 (27H, m), 1.9-2.6 (8H, m), 2.6,2.85(1H, dd), 3 (1H, d), 3.15-3.34 (8H, m), 8.45 (1H, s).

[0945] The following compounds were synthesized using the aboveprocedure:

[0946]N-[(3S)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0947]N-[(3R)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0948]N-[(3S)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0949]N-[(3R)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0950]N-[(3S)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0951]N-[(3R)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0952]N-[(3S)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0953]N-[(3R)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0954]N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0955]N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3R)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0956]N-[1-cis-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0957]N-[1-cis-(4-tert-Butyl-cyclohexyl)-(3R)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0958]N-[(3S)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0959]N-[(3R)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0960]N-[(3S)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0961]N-[(3R)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0962]N-[(3S)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0963]N-[(3R)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0964]N-[(3S)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0965]N-[(3R)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0966]N-[(3S)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0967]N-[(3R)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0968]N-[(3S)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0969]N-[(3R)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0970]N-[(3S)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0971]N-[(3R)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0972]N-[(3S)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0973]N-[(3R)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0974]N-[(3S)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0975]N-[(3R)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0976]N-[(3S)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0977]N-[(3R)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0978]N-[(3S)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0979]N-[(3R)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

Example 21

[0980]N-(2-Benzyloxymethyl-1-cyano-cyclopropyl)-2-cyclohexylmethyl-4-morpholin-4=yl-4-oxo-butyramide

[0981] To a stirred mixture of NaH (60% dispersion in mineral oil, 35.9g, 149.5 mmol) in DME (100 ML) at 0° C., was added a solution of4-benzyloxymethyl-[1,3,2]-dioxathiolane-2,2-dioxide (K. Burgess et al.,J. Org. Chem. 1993, 58, 3767-3768) (17.4 g, 71.2 mmol) and(benzhydrylidene-amino)acetic acid ethyl ester (19.0 g, 71.2 mmol) inDME (100 mL). The mixture was warmed to 55° C. (30 min later, themixture turned to solid and thus 200 mL of DME was added) and stirredfor 4 h. It was allowed to cool to room temperature, slowly poured ontoice in saturated aqueous ammonium chloride solution, extracted withdichloromethane, washed with brine, dried (sodium sulfate) andconcentrated to give crude ester product.

[0982] A mixture of the above ester and p-toluenesulfonic acidmonohydrate (13.5 g, 71.2 mmol) in MeOH (170 mL) and water (25 mL) wasstirred at room temperature for 1 h. It was diluted with water,extracted with dichloromethane, washed with brine, dried (sodiumsulfate) and purified by flash chromatography on silica gel (4 hexane/1EtOAc) to give the desired amino ester (11.0 g, 61.9% in two steps).

[0983] Typical peptide coupling of the above amino ester with(R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid gave thedesired coupled product in 50% yield.

[0984] A mixture of the above intermediate (13.1 g, 25.5 mmol) andlithium hydroxide (1.2 g, 2 equiv.) in MeOH (100 mL) and water (30 mL)was stirred at room temperature overnight. It was diluted with 1N HCl,extracted with dichloromethane, washed with brine, dried (sodiumsulfate) and concentrated to dryness to give the desired carboxylic acid(10.6 g, 86%).

[0985] To a stirred solution of the above acid (11.3 g, 23.3 mmol) inTHF (50 mL) at −10° C. was added triethylamine (3.9 mL, 1.2 equiv.) andethyl chloroformate (2.7 mL, 1.2 equiv.). 20 Min later, ammonia gas wasbubbled through the reaction for 4 h at −20° C. The reaction was allowedto warm to room temperature and stirred overnight. It was concentratedand purified by flash chromatography on silica gel(dichloromethane/MeOH=10/1) to give the desired amide (11.3 g, 100%).

[0986] To a stirred solution of the above amide (178 mg, 0.36 mmol) andtriethylamine (150 ul, 3 equiv.) in dichloromethane (10 mL) at 0° C. wasadded Tf₂O. The mixture was allowed to warm to room temperature andstirred for 20 min. It was washed with brine, dried (sodium sulfate) andpurified by chromatography on silica gel (hexane/ethyl acetate=1/1) togive the title compound (30 mg, 17.8%).

Example 22

[0987]N¹-(1-Cyano-2-dimethylaminomethyl-cyclopropyl)-2-cyclohexylmethyl-N⁴-ethyl-N⁴-(2-methoxy-ethyl)-succinamide

[0988] A mixture of the intermediate amide from Example 21 (10 g, 20.6mmol) and Pd/C (10%, 3 g) in MeOH (150 mL) was shaken under H₂ in a Parrapparatus overnight and filtered. The filtrate was concentrated todryness to give the desired alcohol (7.8 g, 95.8%).

[0989] To a stirred solution of oxalyl chloride (2 M in dichloromethane,7.6 mL, 15.2 mmol) in dichloromethane (30 mL) at −78° C. was added DMSO(2.2 mL, 31 mmol) dropwise. A solution of the above alcohol (6 g, 15.1mmol) in dichloromethane (30 mL) was added. The mixture was allowed towarm to 40° C. in 1 h before triethylamine (8.5 mL, 61 mmol) was added.The mixture was then warmed to room temperature, washed with water andbrine, dried (sodium sulfate) and concentrated to dryness to give thedesired aldehyde (5.5 g, 92%).

[0990] A mixture of the aldehyde from above (1 g, 2.5 mmol),N-benzylmethylamine (0.33 mL, 2.5 mmol) and sodium triacetoxyborohydride(0.81 g, 1.5 equiv.) in dichloromethane (10 mL) was stirred at roomtemperature overnight. The reaction mixture was washed with water,saturated aqueous ammonium chloride and brine, dried (sodium sulfate)and purified by flash chromatography on silica gel(dichloromethane/MeOH=10/1) to give the desired benzyl methylamine (0.84g, 66.8%).

[0991] A solution of the above amine (478 mg, 0.95 mmol) and cyanuricchloride (353 mg, 2 equiv.) in DMF (4 mL) was stirred at roomtemperature for 1 h. The reaction mixture was diluted with water,extracted with dichloromethane, washed with brine, dried (sodiumsulfate) and purified by flash chromatography on silica gel(dichloromethane/MeOH=20/1) to give the title compound (180 mg, 37.4%).

Example 23

[0992]N-(1-Cyano-2-hydroxymethyl-cyclopropyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

[0993] To a stirred solution of the intermediate alcohol from Example 22(1.1 g, 2.7 mmol) and pyridine (0.44 mL, 5.2 mmol) in dichloromethane(15 mL) at 0° C. was added Tf₂O (0.67 mL, 4 mmol) slowly. The mixturewas allowed to warm to room temperature and stirred for 1 h. Thereaction mixture was washed with brine, dried (sodium sulfate) andpurified by chromatography on silica gel (dichloromethane/MeOH=20/1) togive the title compound (0.35 g, 34.6%).

METHODS OF THERAPEUTIC USE

[0994] The compounds of the invention are useful in inhibiting theactivity of cathepsin S, K, F, L and cathepsin B. In doing so, thesecompounds are useful in blocking disease processes mediated by thesecysteine proteases.

[0995] Compounds of this invention effectively block degradation of theinvariant chain to CLIP by cathepsin S, and thus inhibit antigenpresentation and antigen-specific immune responses. Control of antigenspecific immune responses is an attractive means for treating autoimmunediseases and other undesirable T-cell mediated immune responses. Thus,there is provided methods of treatment using the compounds of thisinvention for such conditions. These encompass autoimmune diseases andother diseases involving inappropriate antigen specific immune responsesincluding, but not limited to, rheumatoid arthritis, systemic lupuserythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis,Guillain-Barre syndrome, psoriasis, Grave's disease, myasthenia gravis,scleroderma, glomerulonephritis, atopic dermatitis, insulin-dependentdiabetes mellitus and asthma. The compounds of the invention can also beused to treat other disorders associated with extracellular proteolysissuch as Alzheimer's disease and atherosclerosis. The compounds of theinvention can also be used to treat other disorders associated withinappropriate autoimmune responses, T-cell mediated immune responses, orextracellular proteolysis mediated by cathepsin S, unrelated to thoselisted above or discussed in the Background of the Invention. Therefore,the invention also provides methods of modulating an autoimmune diseasecomprising administering to a patient in need of such treatment apharmaceutically effect amount of a compound according to the invention.

[0996] Compounds of the invention also include inhibition of cathepsinK. In doing so, they may block inappropriate degradation of bonecollagen and other bone matrix proteases. Thus, there is provided amethod for treating diseases where these processes play a role such asosteoporosis. Inhibition of cathepsins F, L and B are also within thescope of the invention due to similarity of the active sites in cysteineproteases as described above.

[0997] For therapeutic use, the compounds of the invention may beadministered in any conventional dosage form in any conventional manner.Routes of administration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

[0998] The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutical compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 15%, but morepreferably at least about 20%, of a compound of formulas (I) or (Ia)(w/w) or a combination thereof. Alternatively, the compounds may beadministered separately (either serially or in parallel). Separatedosing allows for greater flexibility in the dosing regime.

[0999] As mentioned above, dosage forms of the compounds of thisinvention include pharmaceutically acceptable carriers and adjuvantsknown to those of ordinary skill in the art. These carriers andadjuvants include, for example, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 10-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. As theskilled artisan will appreciate, lower or higher doses may be requireddepending on particular factors. For instance, specific dosage andtreatment regimens will depend on factors such as the patient's generalhealth profile, the severity and course of the patient's disorder ordisposition thereto, and the judgment of the treating physician.

ASSESSMENT OF BIOLOGICAL PROPERTIES

[1000] Expression and Purification of Recombinant Human Cathepsin S

[1001] Cloning of Human Cathepsin S:

[1002] U937 RNA was subjected to reverse transcriptase/polymerase chainreaction with primer A (5′cacaatgaaacggctggtttg 3′) and primer B(5′ctagatttctgggtaagaggg 3′) designed to specifically amplify thecathepsin S cDNA. The resulting 900 bp DNA fragment was subcloned intopGEM-T (Promega) and sequenced to confirm its identity. This constructwas used for all subsequent manipulations. This procedure is typical forcloning of known genes and is established in its field.

[1003] Human Pre-Pro-Cat S was removed from pGem-T vector (Promega, 2800Woods Hollow Rd, Madison, Wis. 53711) by digestion with restrictionenzyme SacI, followed by treatment with T4 DNA polymerase to generate ablunt end, and a second restriction enzyme digest with SalI. It wassubcloned into pFastBac1 donor plasmid (GibcoBRL, 8717 Grovemont Cr.,Gaithersburg, Md. 20884) which had been cut with restriction enzymeBamH1 and blunt-ended and then cut with restriction enzyme SalI. Theligation mixture was used to transform DH5a competent cells (GibcoBRL)and plated on LB plates containing 100 ug/ml ampicillin. Colonies weregrown in overnight cultures of LB media containing 50 ug/ml Ampicillin,plasmid DNA isolated and correct insert confirmed by restriction enzymedigestion. Recombinant pFastBac donor plasmid was transformed intoDH10Bac competent cells (GibcoBRL). Large white colonies were pickedfrom LB plates containing 50 ug/ml kanamycin, 7 ug/ml gentamicin, 10ug/ml tetracycline, 100 ug/ml Bluo-gal, and 40 ug/ml IPTG. DNA wasisolated and used to transfect Sf9 insect cells using CellFECTIN reagent(GibcoBRL). Cells and supernatant were harvested after 72 hours. Viralsupernatant was passaged twice and presence of Cat S confirmed by PCR ofthe supernatant.

[1004] SF9 cells were infected with recombinant baculovirus at a MOI of5 for 48-72 hrs. Cell pellet was lysed and incubated in buffer at pH 4.5at 37 for 2 hours to activate Cat S from pro-form to active mature form(Bromme, D & McGrath, M., Protein Science, 1996, 5:789-791.) Presence ofCat S was confirmed by SDS-PAGE and Western blot using rabbit anti-humanproCat S.

[1005] Inhibition of Cathepsin S

[1006] Human recombinant cathepsin S expressed in Baculovirus is used ata final concentration of 10 nM in buffer. Buffer is 50 mM Na Acetate, pH6.5, 2.5 mMEDTA, 2.5 mMTCEP. Enzyme is incubated with either compound orDMSO for 10 min at 37C. Substrate 7-amino-4-methylcoumarin,CBZ-L-valyl-L-valyl-L-arginineamide (custom synthesis by MolecularProbes) is diluted to 20 uM in water (final concentration of 5 uM),added to assay and incubated for additional 10 minutes at 37 C. Compoundactivity is measured by diminished fluorescence compared to DMSO controlwhen read at 360 nm excitation and 460 nm emission.

[1007] Examples listed above were evaluated for inhibition of cathepsinS in the above assay. All had IC₅₀ values of 100 micromolar or below.

[1008] Inhibition of Cathepsin K. F. L and B:

[1009] Inhibition of these enzymes by particular compounds of theinvention may be determined without undue experimentation by using artrecognized methods as provided hereinbelow each of which is incorporatedherein by reference:

[1010] Cathepsin B, and L assays are to be found in the followingreferences:

[1011] 1. Methods in Enzymology, Vol.244, Proteolytic Enzymes: Serineand Cysteine Peptidases, Alan J. Barrett, ed.

[1012] Cathepsin K assay is to be found in the following reference:

[1013] 2. Bromme, D., Okamoto, K., Wang, B. B., and Biroc, S. (1996) J.Biol. Chem. 271, 2126-2132.

[1014] Cathepsin F assays are to be found in the following references:

[1015] 3. Wang, B., Shi, G. P., Yao, P. M., Li, Z., Chapman, H. A., andBromme, D. (1998) J. Biol. Chem. 273, 32000-32008.

[1016] 4. Santamaria, I., Velasco, G., Pendas, A. M., Paz, A., andLopez-Otin, C (1999) J. Biol. Chem. 274, 13800-13809.

[1017] Preferred compounds to be evaluated for inhibition of CathepsinK, F, L and B in the above assays desirably have IC₅₀ values of 100micromolar or below.

What is claimed is:
 1. A compound of formula (I):

wherein: A is —C(O)— or —CH(OR8)—; R1 is C1-8 alkyl, C3-7 cycloalkyl oraryl wherein R1 is optionally substituted by one or more R_(a); R_(a) isselected from the group consisting of C1-8 alkyl, C3-7 cycloalkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl,heteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, C1-8alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-8 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino,aroylamino, C1-8 alkylthio, arylthio, ureido wherein either nitrogenatom may be independently substituted by alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl orphenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino,alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino,arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino whereinthe nitrogen atom may be independently mono or di-substituted by alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo,carboxy, cyano, nitro, amidino and guanidino; R_(a) may be furtheroptionally substituted by one or more R_(b); R_(b) is selected from thegroup consisting of C1-8 alkyl, C3-6 cycloalkyl, aryl, C1-8 alkoxy,aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino; R2 is hydrogen, OR_(i) or C1-5 alkyl; R3 is hydrogen or C1-5alkyl; R4 is hydrogen or C1-5 alkyl; R5 is hydrogen, C1-8 alkyl, C3-7cycloalkyl or aryl wherein R5 is optionally substituted by one or moreR_(c); R_(c) is selected from the group consisting of C1-8 alkyl, C3-7cycloalkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl; heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy,alkanoyl, aroyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy,aroyloxy, carbamoyl wherein the nitrogen atom may be independently monoor di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,C1-8 alkanoylamino, aroylamino, C1-8 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by alkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, alkoxycarbonylamino,aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy,alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino,R_(c) may be further optionally substituted by one or more R_(d); R_(d)is selected from the group consisting of C1-8 alkyl, C3-6 cycloalkyl,aryl, arylalkyl, C1-8 alkoxy, aryloxy, arylalkoxy, aroyl, amino,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R6is hydrogen or lower alkyl said alkyl being optionally interrupted by 1to two heteroatoms selected from the group consisting of N, O and S; R7is hydrogen, C1-8 alkyl said alkyl being optionally interrupted by 1 totwo heteroatoms selected from the group consisting of N, O and S, C3-7cycloalkyl, aryl or cyano, wherein R7 is optionally substituted by oneor more R_(e); R_(e) is selected from the group consisting of C1-8alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl; heteroaryl selected from the group consistingof furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy,arylC1-8alkoxy, heteroarylC1-8alkoxy, C1-8 alkoxycarbonyl,aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-8 alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8alkylthio, arylthio, arylC1-8 alkylthio, ureido wherein either nitrogenatom may be independently substituted by alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyland phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino,alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino,arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino whereinthe nitrogen atom may be independently mono or di-substituted by alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino, R_(e) may be further optionallysubstituted by one or more R_(f); R_(f) is selected from the groupconsisting of C1-8 alkyl, C3-7 cycloalkyl, aryl optionally substitutedby one or more groups selected from halogen, methyl or methoxy,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl,heteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, arylC1-8alkoxy,C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-8 alkyl, aryl, heterocyclyl selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl and indolinyl or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,C1-8 alkanoylamino, aroylamino, C1-8 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by alkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl,phenothiazinyl and phenoxazinyl, alkoxycarbonylamino,aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy,alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; orR6 and R7 together with the carbon they are attached form a 4 to 7membered carbocyclic or heterocyclic ring, the carbocyclic orheterocyclic ring being optionally substituted with one or more R_(g);R_(g) is selected from the group consisting of alkyl, cycloalkyl,phenyl, heteroaryl selected from the group consisting of furanyl,thienyl and pyridinyl, C1-5alkanoyl, aroyl, C1-5alkoxycarbonyl,aryloxycarbonyl, carbamoyl wherein the nitrogen atom may beindependantly mono or disubstituted by C1-5 alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl and piperazinyl or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl,pyridinyl, benzimidazolyl and quinolinyl, C1-5 alkylthio wherein thesulfur atom may be oxidised to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidised to a sulfoxide or sulfone, C1-5alkylaminosulfonyl, arylaminosulfonyl, halogen, hydroxy, oxo, carboxyand cyano, R_(g) may be further optionally substituted by one or moreR_(h); R_(h) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, aryl optionally substituted by one or more groups selectedfrom halogen, C1-5 alkyl or C1-5 alkoxy, heterocyclyl selected from thegroup consisting of piperidinyl, morpholinyl and piperazinyl, heteroarylselected from the group consisting of furanyl, thienyl pyrrolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl,quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl and quinoxalinyl,C1-5 alkoxy, aryloxy, amino wherein the nitrogen atom may beindependently mono or di-substituted by alkyl, aryl, heterocyclylselected from the group consisting of piperidinyl and morpholinyl orheteroaryl selected from the group consisting of furanyl, thienyl andpyridinyl, halogen, hydroxy, oxo, carboxy and cyano; and R8 is hydrogen,alkyl, cycloalkyl-alkyl or arylalkyl; R_(i) is hydrogen or C1-8 alkyl; Xis O or S; and pharmaceutically acceptable salts, esters or tautomersthereof.
 2. The compound according to claim 1 wherein: R1 is C1-5 alkyl,C3-7 cycloalkyl, phenyl, naphthyl, R1 is optionally substituted by oneor more R_(a); R_(a) is selected from the group consisting of C1-5alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl;, heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy,aryloxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy,aroyloxy, carbamoyl wherein the nitrogen atom may be independently monoor di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by alkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byalkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino, R_(a) may be further optionallysubstituted by one or more R_(b); R_(b) is selected from the groupconsisting of C1-5 alkyl, C3-6 cycloalkyl, aryl, C1-5 alkoxy, aryloxy,halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R2is hydrogen, OR_(i) or C1-3 alkyl; R3 is hydrogen or C1-3 alkyl; R4 ishydrogen or C1-3 alkyl; R5 is hydrogen, C1-5 alkyl, C3-7 cycloalkyl oraryl wherein R5 is optionally substituted by one or more R_(c); R_(c) isselected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl,heteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkoxy, aryloxy, C1-5 alkanoyl, aroyl, C1-5alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, C1-5 alkanoylamino, aroylamino, C1-5alkylthio, arylthio, ureido wherein either nitrogen atom may beindependently substituted by C1-5 alkyl, aryl, heterocyclyl selectedfrom the group consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy,arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-5 alkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, amidino andguanidino, R_(c) may be further optionally substituted by one or moreR_(d); R_(d) is selected from the group consisting of C1-5 alkyl, C3-6cycloalkyl, aryl, arylalkyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy,aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino andguanidino; R6 is hydrogen or C1-8 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S; R7 is hydrogen, C1-5 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S, C3-7 cycloalkyl, aryl or cyano, wherein R7 is optionallysubstituted by one or more R_(e); R_(e) is selected from the groupconsisting of C1-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selectedfrom the group consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy,aryloxy, arylC1-5alkoxy, heteroarylC1-5alkoxy, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkanoylamino, aroylamino, C1-5alkylthioarylthioarylC1-5 alkylthio, ureido wherein either nitrogen atommay be independently substituted by C1-5 alkyl, aryl, heterocyclylselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino and guanidino, R_(e) may be further optionallysubstituted by one or more R_(f); R_(f) is selected from the groupconsisting of C1-5 alkyl, C3-7 cycloalkyl, aryl optionally substitutedby one or more groups selected from halogen, methyl or methoxy,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl,heteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy, C1-5alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, C1-5 alkanoylamino, aroylamino, C1-5alkylthio, arylthio, ureido wherein either nitrogen atom may beindependently substituted by C1-5 alkyl, aryl, heterocyclyl selectedfrom the group consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy,arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-5 alkyl, aryl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyland quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidinoand guanidino; or R6 and R7 together with the carbon they are attachedform a carbocyclic ring selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or a heterocyclicring selected from the group consisting of pyrrolidinyl, piperidinyl,hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, pyranyl,thiopyranyl, 1,2-thiazinanyl-1,1-dioxide,1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide andimidazolidinyl-2,4-dione, the carbocyclic or heterocyclic ring beingoptionally substituted with one or more R_(g); R_(g) is selected fromthe group consisting of alkyl, cycloalkyl, phenyl, heteroaryl selectedfrom the group consisting of furanyl and thienyl, C1-3 alkanoyl,benzoyl, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may beindependently mono or disubstituted by C1-5 alkyl, phenyl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl andpiperazinyl or heteroaryl selected from the group consisting of furanyl,thienyl and pyridinyl, C1-3 alkylthio wherein the sulfur atom may beoxidised to a sulfoxide or sulfone, phenylthio wherein the sulfur atommay be oxidised to a sulfoxide or sulfone, C1-5 alkylaminosulfonyl,phenylaminosulfonyl, halogen, hydroxy, carboxy and cyano, R_(g) may befurther optionally substituted by one or more R_(h); R_(h) is selectedfrom the group consisting of C1-3 alkyl, C5-6 cycloalkyl, phenyloptionally substituted by one or more groups selected from halogen, C1-3alkyl and C1-3 alkoxy, piperidinyl, morpholinyl, piperazinyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, benzimidazolyl,quinolinyl, isoquinolinyl, C1-3 alkoxy, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-5 alkyl, phenyl,heterocyclyl selected from the group consisting of piperidinyl andmorpholinyl or heteroaryl selected from the group consisting of furanyl,thienyl and pyridinyl, halogen, hydroxy, oxo and cyano. R8 is hydrogen,C1-8 alkyl, C3-6 cycloalkyl-alkyl or aryl-C1-3 alkyl; and R_(i) ishydrogen or C1-5 alkyl.
 3. The compound according to claim 2 wherein: R1is C1-5 alkyl, C3-7 cycloalkyl, phenyl or naphthyl wherein R1 isoptionally substituted by one or more R_(a); R_(a) is selected from thegroup consisting of C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl,heteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl and isoquinolinyl, C1-5 alkoxy, aryloxy, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,phenyl, naphthyl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and indolinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl and isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5alkylthio, arylthio, ureido wherein either nitrogen atom may beindependently substituted by alkyl or aryl, C1-5 alkoxycarbonylamino,aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by alkyl, aryl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen,hydroxy, oxo, carboxy, cyano and nitro, R_(a) may be further optionallysubstituted by one or more R_(b); R_(b) is selected from the groupconsisting of C1-5 alkyl, C3-6 cycloalkyl, aryl, C1-5 alkoxy, aryloxy,halogen, hydroxy, oxo, carboxy and cyano; R2 is hydrogen, ORi or methyl;R3 is hydrogen or methyl; R4 is hydrogen or methyl; R5 is C1-5 alkyl,C3-7 cycloalkyl or phenyl wherein R5 is optionally substituted by one ormore R_(c); R_(c) is selected from the group consisting of C1-3 alkyl,C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of piperidinyl, morpholinyl and piperazinyl; heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl, C1-5 alkoxy, aryloxy, aroyl, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by C1-5 alkyl,phenyl, naphthyl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl or heteroaryl selected thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy,arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-5 alkyl, phenyl,naphthyl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen,hydroxy, oxo, carboxy and cyano, R_(c) may be further optionallysubstituted by one or more R_(d);. R_(d) is selected from the groupconsisting of C1-5 alkyl, C3-6 cycloalkyl, aryl, arylC1-5alkyl, C1-5alkoxy, aryloxy, arylC1-3alkoxy, aroyl, amino, halogen, hydroxy, oxo,carboxy and cyano; R6 is hydrogen or C1-5 alkyl said alkyl beingoptionally interrupted by 1 to two heteroatoms selected from the groupconsisting of N, O and S; R7 is hydrogen, C1-5 alkyl said alkyl beingoptionally interrupted by 1 to two heteroatoms selected from the groupconsisting of N, O and S, C3-7 cycloalkyl, phenyl, naphthyl or cyano,wherein R7 is optionally substituted by one or more R_(e);. R_(e) isselected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl,phenyl, naphthyl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andindolinyl, heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy,heteroarylC1-5alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, aryl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl andpiperazinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyland isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio,arylthio, arylC1-5 alkylthio, ureido wherein either nitrogen atom may beindependently substituted by C1-5 alkyl, aryl, heterocyclyl selectedfrom the group consisting of piperidinyl, morpholinyl and piperazinyl orheteroaryl selected from the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyland isoquinolinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, R_(e) may befurther optionally substituted by one or more R_(f); R_(f) is selectedfrom the group consisting of C1-5 alkyl, C3-7 cycloalkyl, phenyloptionally substituted by one or more groups selected from halogen,methyl and methoxy, naphthyl optionally substituted by one or moregroups selected from halogen, methyl and methoxy, heterocyclyl selectedfrom the group consisting of pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy,aryloxy, arylC1-5alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, aryl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl andpiperazinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyland isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio,arylthio, ureido wherein either nitrogen atom may be independentlysubstituted by C1-5 alkyl, aryl, heterocyclyl selected from the groupconsisting of piperidinyl, morpholinyl and piperazinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, heterocyclyl selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano; or R6 and R7together with the carbon they are attached form a carbocyclic ringselected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl or a heterocyclic ring selected from thegroup consisting of piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, piperazinyl, pyranyl and thiopyranyl, thecarbocyclic or heterocyclic ring being optionally substituted with oneor more R_(g); R_(g) is selected from the group consisting of C1-3alkyl, C3-6 cycloalkyl, C1-3 alkanoyl, benzoyl, C1-3 alkoxycarbonyl,carbamoyl wherein the nitrogen atom may be independantly mono ordisubstituted by C1-5 alkyl, phenyl, heterocyclyl selected from thegroup consisting of piperidinyl, morpholinyl and piperazinyl orheteroaryl selected from the group consisting of furanyl, thienyl andpyridinyl, halogen, hydroxy, carboxy and cyano, R_(g) may be furtheroptionally substituted by one or more R_(h); R_(h) is selected from thegroup consisting of methyl, phenyl optionally substituted by one or moregroups selected from halogen, methyl and methoxy, piperidinyl,morpholinyl, piperazinyl, pyridinyl, amino wherein the nitrogen atom maybe independently mono or di-substituted by C1-3 alkyl, phenyl,heterocyclyl selected from the group consisting of piperidinyl andmorpholinyl or heteroaryl selected from the group consisting of furanyl,thienyl and pyridinyl, halogen, hydroxy, oxo and cyano; R8 is hydrogen,C1-5 alkyl, C5-6 cycloalkyl-C1-3 alkyl or benzyl; R_(i) is hydrogen ormethyl; and X is O.
 4. A compound according to claim 3 wherein: R1 isC1-5 alkyl, C3-6 cycloalkyl, phenyl or naphthyl wherein R1 is optionallysubstituted by one or more R_(a); R_(a) is selected from the groupconsisting of C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-3alkoxy, phenoxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy,aroyloxy, carbamoyl wherein the nitrogen atom may be independently monoor di-substituted by C1-5 alkyl, phenyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by C1-5alkyl,phenyl or naphthyl, C1-5 alkoxycarbonylamino, C1-5 alkylcarbamoyloxy,arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-5alkyl, phenyl,naphthyl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl or heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen,hydroxy, oxo, carboxy and cyano, R_(a) may be further optionallysubstituted by one or more R_(b); R_(b) is selected from the groupconsisting of C1-3 alkyl, C5-6 cycloalkyl, aryl, C1-3 alkoxy, phenoxy,halogen, hydroxy, oxo, carboxy and cyano; R2 is hydrogen or Ori; R3 ishydrogen; R4 is hydrogen; R5 is C1-5 alkyl, C3-6 cycloalkyl or phenyl,wherein R5 is optionally substituted by one or more R_(c); R_(c) isselected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl,phenyl, naphthyl, heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl and piperazinyl, heteroaryl selected from thegroup consisting of furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl,indolyl, quinolinyl and isoquinolinyl, C1-5 alkoxy, phenoxy, aroyl, C1-5alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the groupconsisting of piperidinyl, morpholinyl and piperazinyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5alkanoylamino, aroylamino, C1-3 alkylthio, phenylthio, ureido whereineither nitrogen atom may be independently substituted by C1-3 alkyl,phenyl or heteroaryl selected the group consisting of furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5alkoxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3 alkyl, phenyl,heterocyclyl selected from the group consisting of piperidinyl,morpholinyl and piperazinyl or heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy andcyano, R_(c) may be further optionally substituted by one or more R_(d);R_(d) is selected from the group consisting of C1-5 alkyl, C5-6cycloalkyl, phenyl, naphthyl, arylC1-3alkyl, C1-5 alkoxy, phenoxy,arylC1-3alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano;R6 is hydrogen or C1-3alkyl said alkyl being optionally interrupted by 1to two heteroatoms selected from the group consisting of N, O and S; R7is hydrogen, C1-5 alkyl said alkyl being optionally interrupted by 1 totwo heteroatoms selected from the group consisting of N, O and S, C3-6cycloalkyl, phenyl or cyano, wherein R7 is optionally substituted by oneor more R_(e); R_(e) is selected from the group consisting of C1-3alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl andpiperazinyl, heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyland isoquinolinyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy,heteroarylC1-3alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, phenyl or heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5alkanoylamino, aroylamino, C1-3 alkylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, arylthio, arylC1-3alkylthio, ureidowherein either nitrogen atom may be independently substituted by C1-5alkyl or phenyl, C1-5 alkoxycarbonylamino, C1-5 alkylsulfonylamino,arylsulfonylamino, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclylselected from the group consisting of piperidinyl, morpholinyl andpiperazinyl or heteroaryl selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, andindolyl, halogen, hydroxy, oxo, carboxy and cyano, R_(e) may be furtheroptionally substituted by one or more R_(f); R_(f) is selected from thegroup consisting of C1-3 alkyl, C5-6 cycloalkyl, phenyl optionallysubstituted by one or more groups selected from halogen and methyl,heterocyclyl selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from thegroup consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl, C1-5 alkoxy,aryloxy, arylC1-3alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl or aryl, C1-5alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by C1-5 alkyl oraryl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl or aryl, halogen, hydroxy, oxo, carboxy and cyano; or R6 andR7 together with the carbon they are attached form a carbocyclic ringselected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl or heterocyclic ring selected from the groupconsisting of piperidinyl, morpholinyl and thiomorpholinyl, thecarbocyclic or heterocyclic ring being optionally substituted with oneor more R_(g); R_(g) is selected from the group consisting of C1-3alkyl, C3-6 cycloalkyl, C1-3 alkanoyl, C1-3 alkoxycarbonyl and carbamoylwherein the nitrogen atom may be independantly mono or disubstituted byC1-5 alkyl; R_(g) may be further optionally substituted by one or moreR_(h); and R_(h) is phenyl or amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl and R8 is hydrogen ormethyl.
 5. The compound according to claim 4 wherein: R1 is C1-3 alkyl,C3-6 cycloalkyl, phenyl, naphthyl, wherein R1 is optionally substitutedby one or more R_(a); R_(a) is selected from the group consisting ofC1-3 alkyl, C5-6 cycloalkyl, phenyl, heterocyclyl selected from thegroup consisting of piperidinyl, morpholinyl and piperazinyl, heteroarylselected from the group consisting of furanyl, thienyl, pyrrolyl,imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-3alkoxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy,aroyloxy, carbamoyl wherein the nitrogen atom may be independently monoor di-substituted by C1-3 alkyl, phenyl or heteroaryl selected from thegroup consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl and benzthiazolyl, C1-5alkanoylamino, aroylamino, C1-3 alkylthio, arylthio, ureido whereineither nitrogen atom may be independently substituted by C1-3alkyl orphenyl, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein thenitrogen atom may be independently mono or di-substituted by C1-3alkyl,phenyl, heterocyclyl selected from the group consisting of piperidinyl,morpholinyl and piperazinyl or heteroaryl selected from the groupconsisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl andisoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, R_(a) may befurther optionally substituted by one or more R_(b); R_(b) is selectedfrom the group consisting of C1-3 alkyl, C5-6 cycloalkyl, C1-3 alkoxy,halogen and hydroxy; R2 is hydrogen: R5 is C1-5 alkyl, C5-6 cycloalkylor phenyl wherein R5 is optionally substituted by one or more R_(c);R_(c) is selected from the group consisting of C1-3 alkyl, C3-6cycloalkyl, phenyl, naphthyl, 4-piperidinyl, 4-morpholinyl, piperazinyl,furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, C1-5alkoxy, phenoxy, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl or phenyl, C1-5alkanoylamino, C1-3 alkylthio, ureido wherein either nitrogen atom maybe independently substituted by C1-3 alkyl or phenyl, C1-5alkoxycarbonylamino, C1-5 alkylsulfonylamino, arylsulfonylamino, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, R_(c)may be further optionally substituted by one or more R_(d); R_(d) isselected from the group consisting of C1-5 alkyl, C5-6 cycloalkyl,phenyl, benzyl, C1-5 alkoxy, phenoxy, benzyloxy, aroyl, halogen,hydroxy, oxo, carboxy and cyano; R6 is hydrogen or C1-3alkyl said alkylbeing optionally interrupted by 1 to two heteroatoms selected from thegroup consisting of N, O and S; R7 is hydrogen, C1-5 alkyl said alkylbeing optionally interrupted by 1 to two heteroatoms selected from thegroup consisting of N, O and S, phenyl or cyano, wherein R7 isoptionally substituted by one or more R_(e); R_(e) is selected from thegroup consisting of C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl,furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, C1-3alkoxy, benzyloxy, pyridylC1-3alkoxy, thienylC1-3alkoxy,furanylC1-3alkoxy, C1-3 alkoxycarbonyl, phenoxyoxycarbonyl, C1-5alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or phenyl, C1-5alkanoylamino, aroylamino, methylthio, benzylthio, ureido wherein eithernitrogen atom may be independently substituted by C1-5 alkyl or phenyl,C1-3 alkoxycarbonylamino, amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl or phenyl, halogen,hydroxy, oxo, carboxy and cyano, R_(e) may be further optionallysubstituted by one or more R_(f); R_(f) is selected from the groupconsisting of C1-3 alkyl, phenyl optionally substituted by one or moregroups selected from the group consisting of halogen and methyl,heterocyclyl selected from the group consisting of piperidinyl,morpholinyl and piperazinyl, heteroaryl selected from the groupconsisting of furanyl, thienyl, pyrrolyl and pyridinyl, C1-3 alkoxy,aryloxy, benzyloxy, C1-5 alkoxycarbonyl, C1-5 alkanoyloxy, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-5 alkyl or phenyl, C1-5 alkanoylamino, aroylamino,C1-5 alkylthio, ureido wherein either nitrogen atom may be independentlysubstituted by C1-5 alkyl or phenyl, C1-5 alkoxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano; or R6and R7 together with the carbon they are attached form cyclopropyl or aheterocyclic ring selected from the group consisting of piperidinyl,pyranyl and thiopyranyl, the cyclopropyl or heterocyclic ring beingoptionally substituted with one or more R_(g); and R_(g) is selectedfrom the group consisting of methyl, benzyl, acetyl, benzoyl,benzyloxycarbonyl and ethoxycarbonyl; and R8 is hydrogen.
 6. Thecompound according to claim 5 wherein: R1 is C3-6 cycloalkyl, phenyl ornaphthyl, wherein R1 is optionally substituted by one or more R_(a);R_(a) is selected from the group consisting of C1-3 alkyl, C5-6cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, C1-3 alkoxy,C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or phenyl, C1-5alkanoylamino, aroylamino, ureido wherein either nitrogen atom may beindependently substituted by C1-3alkyl or phenyl, C1-5alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3alkyl or phenyl,halogen, hydroxy, oxo, carboxy and cyano, R_(a) may be furtheroptionally substituted by one or more R_(b); R_(b) is selected from thegroup consisting of C1-3alkyl, C1-3alkoxy, halogen and hydroxy; R5 isC1-5 alkyl, C5-6 cycloalkyl or phenyl, wherein R5 is optionallysubstituted by one or more groups of the formula R_(c); R_(c) isselected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl,phenyl, naphthyl, 4-piperidinyl, furanyl, thienyl, thiazolyl,imidazolyl, pyridinyl, indolyl, C1-3 alkoxy, C1-5 alkoxycarbonyl, C1-5alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or phenyl, C1-5alkanoylamino, C1-3 alkylthio, C1-3 alkoxycarbonylamino, C1-3alkylsulfonylamino, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy, oxo,carboxy and cyano, R_(c) may be further optionally substituted by one ormore R_(d); R_(d) is selected from the group consisting of C1-3 alkyl,phenyl, benzyl, C1-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen,hydroxy, oxo, carboxy and cyano; wherein the configuration at thestereocenter defined by R4 and R5 and the carbon they are attached to isdefined as L; R6 is hydrogen or C1-2 alkyl said alkyl being optionallyinterrupted by 1 to two heteroatoms selected from the group consistingof N, O and S; R7 is C1-5 alkyl said alkyl being optionally interruptedby 1 to two heteroatoms selected from the group consisting of N, O andS; phenyl or cyano wherein R7 is optionally substituted by one or moregroups of the formula R_(e); R_(e) is selected from the group consistingof methyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl,thiazolyl, imidazolyl, pyridinyl, indolyl, C1-3 alkoxy, benzyloxy,pyridylC1-3alkoxy, thienylC1-3alkoxy, furanylC1-3alkoxy, C1-5alkanoylamino, aroylamino, methylthio, benzylthio, C1-3alkoxycarbonylamino, amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl or phenyl, halogen,hydroxy, oxo, carboxy and cyano, R_(e) may be further optionallysubstituted by one or more R_(f);. R_(f) is selected from the groupconsisting of C1-3 alkyl, phenyl optionally substituted by one or moregroups selected from halogen and methyl, C1-3 alkoxy, aryloxy,benzyloxy, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom maybe independently mono or di-substituted by C1-3 alkyl or phenyl, C1-5alkanoylamino, aroylamino, amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or phenyl, halogen,hydroxy, oxo, carboxy and cyano; or R6 and R7 together with the carbonthey are attached form cyclopropyl or a heterocyclic ring selected fromthe group consisting of piperidinyl and pyranyl, the cyclopropyl orheterocyclic ring being optionally substituted with one or more R_(g);and R_(g) is methyl.
 7. The compound according to claim 6 wherein: R1 iscyclopropyl, cyclohexyl, phenyl or naphthyl wherein R1 is optionallysubstituted by one or more R_(a); R_(a) is selected from the groupconsisting of C1-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl,pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, C1-3 alkoxy, C1-3 alkoxycarbonyl,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl or phenyl, C1-5 alkanoylamino, aroylamino,C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogenatom may be independently mono or di-substituted by C1-3 alkyl, halogen,hydroxy, oxo, carboxy and cyano, R_(a) may be further optionallysubstituted by one or more R_(b); R_(b) is selected from the groupconsisting of C1-3 alkoxy, halogen and hydroxy, R5 is C1-5 alkyl or C5-6cycloalkyl wherein R5 is optionally substituted by one or more R_(c);R_(c) is selected from the group consisting of methyl, C3-6 cycloalkyl,phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, C1-4 alkoxy,C1-5 alkanoylamino, methylthio, halogen, hydroxy, oxo, carboxy andcyano, R_(c) may be further optionally substituted by one or more R_(d);R_(d) is selected from the group consisting of methyl, phenyl, benzyl,methoxy, phenoxy, benzyloxy, benzoyl, halogen and hydroxy; R7 is C1-5alkyl or phenyl, wherein R7 is optionally substituted by one or moreR_(e); R_(e) is selected from the group consisting of C3-6 cycloalkyl,phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy,benzyloxy, C1-3 alkanoylamino, methylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, benzylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, methoxycarbonylamino, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, halogen, hydroxy, carboxy and cyano, R_(e) may be furtheroptionally substituted by one or more R_(f); R_(f) is selected from thegroup consisting of methyl, phenyl optionally substituted by one or moregroups selected from halogen or methyl, methoxy, phenoxy, benzyloxy,methoxycarbonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy andcarboxy; or R6 and R7 together with the carbon they are attached form acyclopropyl ring.
 8. The compound according to claim 7 wherein: R1 iscyclopropyl, cyclohexyl, phenyl or naphthyl, wherein R1 is optionallysubstituted by one or more R_(a); R_(a) is selected from the groupconsisting of pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy,methoxycarbonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-3 alkyl, halogen, hydroxy and carboxy,R_(a) may be further optionally substituted by one or more R_(b); R_(b)is selected from the group consisting of methoxy, halogen and hydroxy;R_(c) is selected from the group consisting of methyl, C3-6 cycloalkyl,phenyl, naphthyl, C1-4 alkoxy, C1-3 alkanoylamino, methylthio, halogen,hydroxy, oxo, carboxy and cyano, R_(c) may be further optionallysubstituted by one or more R_(d); R_(d) is selected from the groupconsisting of methyl, phenyl, methoxy, halogen and hydroxy; R6 ishydrogen; R_(e) is selected from the group consisting of C5-6cycloalkyl, phenyl, naphthyl, thienyl, indolyl, methoxy, benzyloxy,methylthio, benzylthio, methoxycarbonylamino, halogen, hydroxy, carboxyand cyano, R_(e) may be further optionally substituted by one or moreR_(f); and R_(f) is selected from the group consisting of methyl, phenyloptionally substituted by halogen, methoxy, phenoxy, benzyloxy,methoxycarbonyl, halogen, hydroxy and carboxy.
 9. The compound accordingto claim 8 wherein: R1 is phenyl; R5 is C1-5 alkyl wherein R5 isoptionally substituted by one or more R_(c); R_(c) is selected from thegroup consisting of C3-6 cycloalkyl, phenyl and 2-naphthyl, R_(c) may befurther optionally substituted by one or more R_(d); R_(d) is selectedfrom the group consisting of methyl and halogen; R_(e) is selected fromthe group consisting of C5-6 cycloalkyl, phenyl, naphthyl, indolyl,benzyloxy, methylthio, benzylthiohalogen and carboxy, R_(e) may befurther optionally substituted by one or more R_(f); and R_(f) isselected from the group consisting of methyl, methoxy, methoxycarbonyl,halogen and hydroxy.
 10. A compound selected from the group consistingof:N-(1-benzyl-3-cyano-pyrrolidin-3-yl)-4-(4-chloro-phenyl)-2-cyclohexylmethyl-4-oxo-butyramide:

N-(1-benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(4-methoxy-phenyl)-4-oxo-butyramide:

and the pharmaceutically acceptable salts, esters or tautomers thereof.11. A pharmaceutical composition comprising a pharmaceutically effectiveamount of a compound according to claim 1 .
 12. A method of modulatingan autoimmune disease, said method comprising administering to a patientin need of such treatment a pharmaceutically effect amount of a compoundaccording to claim 1 .
 13. The method according to claim 12 wherein theautoimmune disease is selected from the group consisting of: rheumatoidarthritis, systemic lupus erythematosus, Crohn's disease, ulcerativecolitis, multiple sclerosis, Guillain-Barre syndrome, psoriasis, Grave'sdisease, myasthenia gravis, scleroderma, glomerulonephritis, atopicdermatitis and insulin-dependent diabetes mellitus.
 14. A method oftreating Alzheimer's disease comprising administering to a patient inneed of such treatment a pharmaceutically effective amount of a compoundaccording to claim 1 .
 15. A method of treating atherosclerosiscomprising administering to a patient in need of such treatment apharmaceutically effective amount of a compound according to claim 1 .16. A method of making a compound of the formula (I) according to claim1 comprising: a) reacting a carboxylic acid compound shown below with anamine R₁H in the presence of a coupling reagant selected from the groupconsisting of EDC and HOBT, in a suitable solvent;

b) hydrolyzing the product of step a) with aqueous base or acid toproduce:

c) reacting the product of step b) with an amino nitrile compound shownbelow in the presence of EDC as a coupling reagent, in a suitablesolvent,

OR d) reacting the product of step b) with an amino amide compound shownbelow in the presence of EDC as a coupling reagant, in a suitablesolvent followed by dehydration of the primary amide to yield a nitrilegroup

wherein X is O, R1, R2, R3, R4, R5, R6, R7, and A are as defined inclaim 1 .
 17. A method of making a compound of the formula (I) accordingto claim 1 comprising: a) reacting an activated amide compound shownbelow with an aryl organometallic reagant:

b) hydrolyzing the product of step a) with aqueous base or acid toproduce:

c) reacting the product of step b) with an amino nitrile compound shownbelow in the presence of EDC as a coupling reagant , in a suitablesolvent,

or d) reacting the product of step b) with an amino amide compound shownbelow in the presence of EDC as a coupling reagant, in a suitablesolvent, followed by dehydration of the primary amide to yield a nitrilegroup,

and optionally reducing the carbonyl group attached to R1, to produce acompound of the formula (I) wherein X is O, and R1, R2, R3, R4, R5, R6,R7 and A are as defined in claim 1 .